Pyridineamine compounds useful as Pim kinase inhibitors

ABSTRACT

The present disclosure describes pyridineamine compounds, as well as their compositions and methods of use. The compounds inhibit the activity of the Pim kinases, and are useful in the treatment of diseases related to the activity of Pim kinases including, e.g., cancer and other diseases.

TECHNICAL FIELD

The present application is concerned with pharmaceutically usefulpyridineamine compounds, as well as their compositions and methods ofuse. The compounds inhibit the activity of Pim kinases and are thereforeuseful in the treatment of diseases related to the activity of Pimkinases including, e.g., cancers and other diseases.

BACKGROUND

Protein kinases regulate diverse biological processes including cellgrowth, survival, differentiation, organ formation, morphogenesis,neovascularization, tissue repair, and regeneration, among others.Protein kinases also play specialized roles in a host of human diseasesincluding cancer. The three members of the Pim kinase family, oneexample of a protein kinase family, were initially identified aspreferential integration sites of Moloney leukemia virus in mouse modelsof cancer. Although possessing modest but measurable oncogenic activityalone, they potentiate pro-proliferative and pro-survival oncogenes,e.g., causing a dramatic acceleration of lymphomagenesis inMyc-transgenic or Bcl2-transgenic mice. Mikkers et al., Nature Genet.,2002, 32, 153-159; Shinto et al., Oncogene, 1995, 11, 1729-35.

The three non-receptor serine/threonine kinases Pim1, Pim2 and Pim3regulate cell proliferation and survival by impacting gene transcriptionand protein translation. Zippo, et al., Nature Cell Biol., 2007, 9,932-44; Schatz, et al., J. Exp. Med., 2011, 208, 1799-1807. As opposedto numerous other protein kinases which require activation byphosphorylation, the Pim kinases are constitutively activated and familymembers have overlapping substrate targets and biological functions,with differences between family members dictated, in part, by theirvaried tissue distribution. Expression of the Pim kinases is induced bycytokines and growth factors. Among the cytokines activating Pim kinaseexpression are cytokines which signal through the JAK/STAT pathway. Pimkinases act in parallel to the PI3K/AKT pathway, and they share severalphosphorylation targets (e.g., pBAD, p4EBP1). Inhibitors of Pim kinasesmay therefore potentiate regimens including inhibitors of either the JAKpathway or the PI3K/AKT pathway.

Overexpression of Pim kinases is detected in a wide variety ofhematologic and solid cancers. Overexpression of various family membershave been noted in multiple myeloma, AML, pancreatic and hepatocellularcancers. Claudio et al., Blood, 2002, 100, 2175-86; Amson et al., Proc.Nat. Acad. Sci., USA, 1989, 86, 8857-61; Mizuki et al., Blood, 2003,101, 3164-73; Li et al., Canc. Res., 2006, 66, 6741-7; Fujii et al.,Int. J. Canc., 2005, 114, 209-18. Pim1 overexpression is associated withpoor prognosis in mantle cell lymphoma, esophageal and head and neckcancers. Hsi et al., Leuk. Lymph., 2008, 49, 2081-90; Liu et al., J.Surg. Oncol., 2010, 102, 683-88; Peltola et al., Neoplasia, 2009, 11,629-36. Pim2 overexpression is associated with an aggressive clinicalcourse in a subset of DLBCL patients. Gomez-Abad et al., Blood, 2011,118, 5517-27. Overexpression is often seen where Myc is overexpressedand Pim kinases can convey resistance to traditional chemotherapeuticagents and radiation. Chen et al., Blood, 2009, 114, 4150-57; Isaac etal., Drug Resis. Updates, 2011, 14, 203-11; Hsu et al., Cancer Lett.,2012, 319, 214; Peltola et al., Neoplasia, 2009, 11, 629-36.

As such, these data indicate that inhibition of Pim kinases will beuseful to provide therapeutic benefit in cancer patients.

Data from mice deficient for one or multiple Pim kinase family memberssuggests that pan-Pim inhibitor would have a favorable toxicity profile.Triple knockout mice are viable, but are slightly smaller than theirwild type littermates. Mikkers et al., Mol. Cell. Biol., 2004, 24.6104-15. Since Pim kinases are also involved in a variety of immunologicand inflammatory responses and these indications require drug agentswith fewer side effects, Pim kinase inhibitors are expected to be usefulin treating patients with colitis (Shen et al., Dig. Dis. Sci., 2012,57, 1822-31), peanut allergy (Wang et al., J. All. Clin. Immunol., 2012,130, 932-44), multiple sclerosis and lupus (Davis et al., “SmallMolecule Dual Antagonist of Pim 1 and 3 Kinases Ameliorate ExperimentalAutoimmune Encephalomyelitis”, 26^(th) Congress of the EuropeanCommittee for Treatment and Research in Multiple Sclerosis, 13-16 Oct.2010, Gothenburg, Sweden, Poster P436; Robinson et al., J. Immunol.,2012, 188, 119.9) and rheumatoid arthritis (Yang et al., Immunol. 2010,131, 174-182) and other immunological and inflammatory disorders.

The Pim kinases have therefore been identified as useful targets fordrug development efforts. Swords et al., Curr. Drug Targets, 2011,12(14), 2059-66; Merkel et al., Exp. Opin. Investig. Drugs, 2012, 21,425-38; Morwick et al., Exp. Opin. Ther. Patents, 2010, 20(2), 193-212.

Accordingly, there is a need for new compounds that inhibit Pim kinases.The present application describes new inhibitors of Pim kinases that areuseful for treating diseases associated with the expression or activityof one or more Pim kinases, e.g., cancer and other diseases.

SUMMARY

The present disclosure provides, inter alia, a compound of Formula (I):

or a pharmaceutically acceptable salt thereof; wherein the variables areas defined below.

The present disclosure also provides a pharmaceutical compositioncomprising a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, and at least one pharmaceutically acceptable carrier.

The present disclosure also provides methods of treating cancer andother diseases comprising administering to a patient a therapeuticallyeffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof.

The details of one or more embodiments are set forth in the descriptionbelow. Other features, objects and advantages will be apparent from thedescription and from the claims.

DETAILED DESCRIPTION I. Compounds

The present disclosure provides, inter alia, a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

X is N or CH;

ring A is C₆₋₁₀ aryl or 5-10 membered heteroaryl, said heteroaryl groupconsisting of one or more carbon atoms and 1, 2, or 3 heteroatomsselected from N, O and S, wherein the C₆₋₁₀ aryl or 5-10 memberedheteroaryl is optionally substituted with 1 or 2 substituentsindependently selected from R^(A);

R^(A) is halogen, cyano, amino, or C₁₋₃ alkyl;

n is 0 or 1;

Cy^(A), when present, is selected from C₆₋₁₀ aryl, 5-10 memberedheteroaryl, C₃₋₇ cycloalkyl, and 4-10 membered heterocycloalkyl, whereinthe ring atoms of the 5-10 membered heteroaryl or 4-10 memberedheterocycloalkyl forming Cy^(A) consist of one or more carbon atoms and1, 2, or 3 heteroatoms selected from N, O and S, and wherein the C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₇ cycloalkyl, and 4-10 memberedheterocycloalkyl forming Cy^(A) are each optionally substituted by 1, 2or 3 substituents independently selected from R^(CyA);

R^(CyA) is halogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄haloalkyl, Cy^(B), -L-Cy^(B), ═O, CN, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),NR^(c1)R^(d1) NR^(c1)C(O)R^(b1)NR^(c1)C(O)NR^(c1)R^(d1),NR^(c1)C(O)OR^(a1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),NR^(c1)S(O)₂R^(b1) or S(O)₂NR^(c1)R^(d1); wherein the C₁₋₄ alkyl, C₂₋₄alkenyl, and C₂₋₄ alkynyl forming R^(CyA) are each optionallysubstituted with 1, 2 or 3 substituents independently selected fromhalogen, C₁₋₃ haloalkyl, CN, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),NR^(c1)R^(d1) NR^(c1)C(O)R^(b1), NR^(c1)C(O)NR^(c1)R^(d1),NR^(c1)C(O)OR^(a1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),NR^(c1)S(O)₂R^(b1) and S(O)₂NR^(c1)R^(d1);

Cy^(B) is selected from C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₇cycloalkyl, and 4-10 membered heterocycloalkyl, wherein the ring atomsof the 5-10 membered heteroaryl or 4-10 membered heterocycloalkylforming Cy^(A) consist of one or more carbon atoms and 1, 2, or 3heteroatoms selected from N, O and S, and wherein the C₆₋₁₀ aryl, 5-10membered heteroaryl, C₃₋₇ cycloalkyl, and 4-10 membered heterocycloalkylforming Cy^(B) are each optionally substituted with 1, 2, or 3substituents independently selected from R^(CyB);

R^(CyB) is halogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄haloalkyl, CN, OH, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2),C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2),NR^(c2)C(O)R^(b2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2) orS(O)₂NR^(c2)R^(d2), wherein the C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄alkynyl forming R^(CyB) are each optionally substituted with 1, 2 or 3substituents independently selected from halogen, C₁₋₃ haloalkyl, CN,OH, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)NR^(c2)R^(d2) NR^(c2)C(O)OR^(a2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2) andS(O)₂NR^(c2)R^(d2);

L is C₁₋₄ alkylene, L¹-O-L¹, L¹-C(═O)-L, L¹-OC(═O)-L¹, L¹-C(═O)O-L,L-NHC(═O)-L¹, L¹-C(═O)NH-L¹, L¹-NH-L¹, L¹-N(CH₃)-L¹, L¹-NHC(═O)NH-L¹,L¹-NHC(═O)O-L¹, L¹-S-L, L¹-S(═O)-L¹, L¹-S(═O)₂-L¹, L¹-NHS(═O)₂-L¹,L¹-S(═O)₂NH-L¹, L¹-NHS(═O)₂NH-L¹, wherein L¹, at each occurrence, isindependently selected from a bond and C₁₋₂ alkylene; and wherein theC₁₋₂ alkylene forming L¹ is optionally substituted with 1 or 2substituents independently selected from F, Cl, CN, OH, O(C₁₋₃ alkyl),NH₂, NH(C₁₋₃ alkyl) and N(C₁₋₃ alkyl)₂;

R¹ is H, F, Cl, CN, OH, C₁₋₃ alkoxy, —OC(O)O(C₁₋₃ alkyl), —OC(O)NH(C₁₋₃alkyl), C₁₋₃ alkyl, C₁₋₃ haloalkyl, or C₃₋₆ cycloalkyl;

R² is H, C₁₋₃ alkyl, C₁₋₃ haloalkyl or cyclopropyl;

R³, R⁴, and R⁵ are each independently selected from H, halogen, OH, CN,amino, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄haloalkyl and C₁₋₄ haloalkoxy; alternatively, R⁴ and R⁵ in combination,together with the carbon atoms to which they are attached, form a 5, 6,or 7-membered fused aryl, a 5, 6, or 7-membered fused cycloalkyl, a 5,6, or 7-membered fused heteroaryl, or a 5, 6, or 7-membered fusedheterocycloalkyl, each optionally substituted by 1, 2 or 3 substituentsindependently selected from halogen, OH, CN, amino, NH(C₁₋₄ alkyl),N(C₁₋₄ alkyl)₂, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl and C₁₋₄haloalkoxy;

R⁶ and R⁷ are each independently selected from H, halogen, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₁₋₄ haloalkyl; wherein said C₁₋₄ alkylforming R⁶ or R⁷ is optionally substituted with 1, 2, or 3 substituentsindependently selected from halogen, OH, CN, C₁₋₃ haloalkyl, C₁₋₄alkoxy, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1) andS(O)₂NR^(c1)R^(d1);

alternatively, R⁶ and R⁷, together with the carbon atom to which theyare both attached, form a C₃₋₆ cycloalkyl group that is optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalogen, OH, CN, and C₁₋₄ alkyl;

R^(a1), R^(b1), R^(c1) and R^(d1), at each occurrence, are independentlyselected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, wherein saidC₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl groups forming R^(a1), R^(b1),R^(c1) and R^(d1) are each optionally substituted with 1, 2, or 3substituents independently selected from C₁₋₄ alkyl, halo, CN, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2)NR^(c2)C(O)NR^(c2)R^(d2) NR^(c2)C(O)OR^(a2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2) andS(O)₂NR^(c2)R^(d2);

or R^(c1) and R^(d1) attached to the same N atom, together with the Natom to which they are both attached, form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group that is optionally substituted with 1, 2, or 3substituents independently selected from C₁₋₆ alkyl, halo, CN, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2) NR^(c2)C(O)R^(b2)NR^(c2)C(O)NR^(c2)R^(d2) NR^(c2)C(O)OR^(a2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2) andS(O)₂NR^(c2)R^(d2); and

R^(a2), R^(b2), R^(c2) and R^(d2) are each independently selected fromH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, whereinsaid C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl formingR^(a2), R^(b2), R^(c2) and R^(d2) are each optionally substituted with1, 2, or 3 substituents independently selected from halo, OH, CN, amino,NH(C₁₋₆ alkyl), N(C₁₋₆ alkyl)₂, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyland C₁₋₆ haloalkoxy.

In some embodiments, ring A is C₆₋₁₀ aryl optionally substituted with 1or 2 substituents each independently selected from R^(A).

In some embodiments, phenyl optionally substituted with 1 or 2substituents each independently selected from R^(A).

In some embodiments, ring A is 5-10 membered heteroaryl optionallysubstituted with 1 or 2 substituents each independently selected fromR^(A).

In some embodiments, ring A is a pyridinyl, pyrimidinyl, thiazolyl,quinolinyl, or furopyridinyl, each optionally substituted with 1 or 2substituents each independently selected from R^(A).

In some embodiments, each R^(A) is independently selected from F, NH₂,and isopropyl.

In some embodiments, each R^(A) is F.

In some embodiments, n is 0.

In some embodiments, n is 1.

In some embodiments, Cy^(A) is C₆₋₁₀ aryl optionally substituted by 1,2, or 3 substituents independently selected from R^(CyA).

In some embodiments, Cy^(A) is phenyl optionally substituted by 1, 2, or3 substituents independently selected from R^(CyA).

In some embodiments, Cy^(A) is 2-fluorophenyl optionally substituted by1 or 2 substituents independently selected from R^(CyA).

In some embodiments, Cy^(A) is 5-10 membered heteroaryl optionallysubstituted by 1, 2, or 3 substituents independently selected fromR^(CyA).

In some embodiments, Cy^(A) is pyridinyl, benzothienyl, indolyl,dihydroindolyl, dihydrobenzofuranyl, imidazopyridinyl, or quinolinyl,each optionally substituted by 1, 2, or 3 substituents independentlyselected from R^(CyA).

In some embodiments, Cy^(A) is pyridinyl, benzothien-5-yl, indolyl,dihydroindol-6-yl, 1,3-dihydro-2H-indolinyl, 2,3-dihydrobenzofuran-6-yl,imidazo[1,2-a]pyridin-7-yl, or quinolinyl, each optionally substitutedby 1, 2, or 3 substituents independently selected from R^(CyA).

In some embodiments, Cy^(A) is C₃₋₇ cycloalkyl optionally substituted by1, 2, or 3 substituents independently selected from R^(CyA).

In some embodiments, Cy^(A) is cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or cyclohexenyl, each optionally substituted by 1, 2, or 3substituents independently selected from R^(CyA).

In some embodiments, Cy^(A) is 4-10 membered heterocycloalkyl optionallysubstituted by 1, 2, or 3 substituents independently selected fromR^(CyA).

In some embodiments, the compound is according to any one of thefollowing formulae (II-A) to (II-C):

wherein each n1 is 0, 1, or 2.

In some embodiments, the compound is according to any one of thefollowing formulae (II-D) to (II-K):

wherein each n1 is 0, 1, or 2.

In some embodiments, n1 is 0.

In some embodiments, n1 is 1

In some embodiments, the compound is according to any one of thefollowing formulae (II-DA) to (II-KA):

In some embodiments, the compound is according to any one of thefollowing formulae (III-A) and (III-B):

In some embodiments, the compound is according to any one of thefollowing formulae (IV-A) to (IV-C):

wherein each n2 is 0 or 1.

In some embodiments, the compound is according to any one of thefollowing formulae (V-A) to (V-C):

In some embodiments, each R^(CyA) is halogen, C₁₋₄ alkyl, Cy^(B),-L-Cy^(B), CN, or OR^(a1); wherein each C₁₋₄ alkyl forming R^(CyA) isoptionally substituted with 1, 2, or 3 substituents independentlyselected from halogen, OR^(a1) and NR^(c1)R^(d1).

In some embodiments, Cy^(A) is substituted by 1, 2 or 3 substituentswherein one of the substituents is selected from Cy^(B).

In some embodiments, Cy^(A) is substituted by 1, 2 or 3 substituentswherein one of the substituents is selected from -L-Cy^(B).

In some embodiments, Cy^(A) is substituted by 1 substituent wherein thesubstituent is selected from R^(CyA).

In some embodiments, Cy^(A) is substituted by 1 substituent wherein thesubstituent is selected from Cy^(B).

In some embodiments, Cy^(A) is substituted by 1 substituent wherein thesubstituent is selected from -L-Cy^(B).

In some embodiments, L is C₁₋₄ alkylene, L¹-O-L¹, L¹-NH-L¹ orL¹-N(CH₃)-L¹.

In some embodiments, each L¹ is independently selected from a bond andC₁₋₂ alkylene.

In some embodiments, each L¹ is a bond.

In some embodiments, L is C₁₋₄ alkylene.

In some embodiments, L is CH₂.

In some embodiments, L is O.

In some embodiments, Cy^(B) is C₆₋₁₀ aryl optionally substituted with 1,2, or 3 substituents independently selected from R^(CyB).

In some embodiments, Cy^(B) is phenyl optionally substituted with 1, 2,or 3 substituents independently selected from R^(CyB).

In some embodiments, Cy^(B) is 5-10 membered heteroaryl, optionallysubstituted with 1, 2, or 3 substituents independently selected fromR^(CyB).

In some embodiments, Cy^(B) is pyridinyl, pyrazolyl, or quinolinyl, eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from R^(CyB).

In some embodiments, Cy^(B) is C₃₋₇ cycloalkyl, optionally substitutedwith 1, 2, or 3 substituents independently selected from R^(CyB).

In some embodiments, Cy^(B) is cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or cyclohexenyl, each optionally substituted with 1, 2, or 3substituents independently selected from R^(CyB).

In some embodiments, Cy^(B) is 4-10 membered heterocycloalkyl,optionally substituted with 1, 2, or 3 substituents independentlyselected from R^(CyB).

In some embodiments, Cy^(B) is tetrahydrofuranyl, tetrahydropyranyl,morpholinyl, azetidinyl, pyrrolidinyl, or piperidinyl, each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR^(CyB).

In some embodiments, R^(CyB) is H, halogen, C₁₋₄ alkyl, CN, OH, orOR^(a2).

In some embodiments, R¹ is H, F, or OH.

In some embodiments, R¹ is H.

In some embodiments, R¹ is OH.

In some embodiments, R² is H.

In some embodiments, R² is C₁₋₃ alkyl.

In some embodiments, R² is methyl.

In some embodiments, R² is C₁₋₃ haloalkyl.

In some embodiments, R² is trifluoromethyl.

In some embodiments, R² is cyclopropyl.

In some embodiments, the ring substituted by R¹ and R² is selected fromrings of the following formulae (B-1) to (B-26):

In some embodiments, R³, R⁴, and R⁵ are each independently selected fromH, halo, OH, CN, amino, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkyl, C₁₋₄alkoxy, C₁₋₄ haloalkyl and C₁₋₄ haloalkoxy.

In some embodiments, R³ is hydrogen.

In some embodiments, R⁴ is hydrogen.

In some embodiments, R⁵ is H.

In some embodiments, R⁶ is selected from H, halogen, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, and C₁₋₄ haloalkyl; wherein said C₁₋₄ alkylforming R⁶ is optionally substituted with 1, 2 or 3 substituents eachindependently selected from halogen, OH, CN, C₁₋₃ haloalkyl, C₁₋₄alkoxy, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1) andS(O)₂NR^(c1)R^(d1); and wherein R⁷ is H or C₁₋₄ alkyl.

In some embodiments, R⁶ and R⁷ are each independently selected from Hand C₁₋₄ alkyl.

In some embodiments, R⁶ is H.

In some embodiments, R⁷ is H.

In some embodiments, R⁶ and R⁷, together with the carbon atom to whichthey are both attached, form a C₃₋₆ cycloalkyl group that is optionallysubstituted with 1, 2 or 3 substituents each independently selected fromhalogen, OH, CN, and C₁₋₄ alkyl.

In some embodiments, R⁶ and R⁷, together with the carbon atom to whichthey are both attached, form an unsubstituted C₃₋₆ cycloalkyl.

In some embodiments, R⁶ and R⁷, together with the carbon atom to whichthey are both attached, form an unsubstituted cyclopropyl group.

In some embodiments, R^(a1), R^(b1), R^(c1), R^(d1), R^(a2), R^(b2),R^(c2) and R^(d2) are each independently selected from H and C₁₋₆ alkyl.

Examples of the compounds of Formula (I) include the following compoundsand or pharmaceutically acceptable salts thereof:

-   3-amino-1-{3-[({6-[2,6-difluoro-4-(3-hydroxytetrahydrofuran-3-yl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;-   3-amino-1-(3-(((6-(2,6-difluoro-4-(1-hydroxycyclobutyl)phenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;-   3-amino-1-(3-(((6-(2,6-difluoro-4-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;-   3-(4-{6-[({4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)tetrahydrofuran-3-ol;-   1-(4-(6-((4-(3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-3,5-difluorophenyl)cyclobutanol;-   4-(4-(6-((4-(3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-3,5-difluorophenyl)tetrahydro-2H-pyran-4-ol;-   1-(4-{6-[({4-[3-amino-5-(trifluoromethyl)piperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)cyclobutanol;-   3-amino-1-{3-[({6-[2,6-difluoro-4-(1-hydroxycyclopropyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;-   3-amino-1-(3-(((6-(2,6-difluoro-3-(1-hydroxycyclopropyl)phenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;-   1-(4-{6-[({4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)cyclopropanol;-   1-(3-(6-((4-(3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-2,4-difluorophenyl)cyclopropanol;-   3-amino-1-{3-[({6-[2,6-difluoro-4-(2-hydroxy-2-methylpropyl)phenyl]-5-fluoropyridin-2-yl)}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;-   1-(4-{6-[({4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)-2-methylpropan-2-ol;-   3-amino-1-[3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-4-ol;-   3-amino-1-(3-(((5-fluoro-6-(2-fluoro-6-methoxyphenyl)pyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;-   3-amino-5-methyl-1-(3-(((3,3′,5′-trifluoro-[2,4′-bipyridin]-6-yl)methyl)amino)pyridin-4-yl)piperidin-4-ol;-   2-(6-((4-(3-amino-4-hydroxy-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-3-fluorobenzonitrile;-   3-amino-1-(3-(((5-fluoro-6-(2-fluorophenyl)pyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;-   4-[3-amino-5-methylpiperidin-1-yl]-N-{[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}pyridin-3-amine;-   4-(3-amino-5-methylpiperidin-1-yl)-N-((5-fluoro-6-(2-fluoro-6-methoxyphenyl)pyridin-2-yl)methyl)pyridin-3-amine;-   4-(3-amino-5-methylpiperidin-1-yl)-N-((3,3′,5′-trifluoro-2,4′-bipyridin-6-yl)methyl)pyridin-3-amine;-   2-(6-((4-(3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-3-fluorobenzonitrile;-   4-(3-amino-5-methylpiperidin-1-yl)-N-((5-fluoro-6-(2-fluorophenyl)pyridin-2-yl)methyl)pyridin-3-amine;-   2-(4-{6-[({4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)-2-methylpropanenitrile;-   2-(4-{6-[({4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)-2-methylpropanenitrile;-   3-amino-5-methyl-1-(3-{[(2′,6,6′-trifluorobiphenyl-3-yl)methyl]amino}pyridin-4-yl)piperidin-4-ol;-   4-[3-amino-5-methylpiperidin-1-yl]-N-[(2′,6,6′-trifluorobiphenyl-3-yl)methyl]pyridin-3-amine;-   1-(5′-((4-(3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-2,2′,6-trifluorobiphenyl-4-yl)cyclobutanol;-   4-(5′-((4-(3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-2,2′,6-trifluorobiphenyl-4-yl)tetrahydro-2H-pyran-4-ol;-   3-amino-1-[3-({[6-(2,6-difluorophenyl)pyridin-2-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-4-ol;-   4-[3-amino-5-methylpiperidin-1-yl]-N-{[6-(2,6-difluorophenyl)pyridin-2-yl]methyl}pyridin-3-amine;-   3-amino-1-[3-({[2-(2,6-difluorophenyl)pyrimidin-4-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-4-ol;-   4-[3-amino-5-methylpiperidin-1-yl]-N-{[2-(2,6-difluorophenyl)pyrimidin-4-yl]methyl}pyridin-3-amine;-   3-amino-1-(3-(((6-(2,6-difluoro-4-morpholinophenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;-   4-(3-amino-5-methylpiperidin-1-yl)-N-((6-(2,6-difluoro-4-morpholinophenyl)-5-fluoropyridin-2-yl)methyl)pyridin-3-amine;-   4-(3-amino-5-(trifluoromethyl)piperidin-1-yl)-N-((6-(2,6-difluoro-4-morpholinophenyl)-5-fluoropyridin-2-yl)methyl)pyridin-3-amine;-   3-amino-1-{3-[({6-[2,6-difluoro-4-(hydroxymethyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;-   (4-{6-[({4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)methanol;-   3-amino-1-[3-({[6-(5,7-difluoroquinolin-6-yl)-5-fluoropyridin-2-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-4-ol;-   4-[3-amino-5-methylpiperidin-1-yl]-N-{[6-(5,7-difluoroquinolin-6-yl)-5-fluoropyridin-2-yl]methyl}pyridin-3-amine;-   3-amino-1-{3-[({6-[2,6-difluoro-4-(morpholin-4-ylmethyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;-   3-amino-1-(3-(((6-(2,6-difluoro-4-((methylamino)methyl)phenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;-   3-amino-1-(3-(((6-(4-(azetidin-1-ylmethyl)-2,6-difluorophenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;-   3-amino-1-(3-(((6-(2,6-difluoro-4-((3-hydroxypyrrolidin-1-yl)methyl)phenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;-   1-(4-(6-((4-(3-amino-4-hydroxy-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-3,5-difluorobenzyl)pyrrolidine-3-carbonitrile;-   3-amino-1-(3-(((6-(2,6-difluoro-4-((3-fluoropyrrolidin-1-yl)methyl)phenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;-   4-[3-amino-5-methylpiperidin-1-yl]-N-({6-[2,6-difluoro-4-(morpholin-4-ylmethyl)phenyl]-5-fluoropyridin-2-yl}methyl)pyridin-3-amine;-   4-(3-amino-5-methylpiperidin-1-yl)-N-((6-(2,6-difluoro-4-((methylamino)methyl)phenyl)-5-fluoropyridin-2-yl)methyl)pyridin-3-amine;-   4-(3-amino-5-methylpiperidin-1-yl)-N-((6-(4-(azetidin-1-ylmethyl)-2,6-difluorophenyl)-5-fluoropyridin-2-yl)methyl)pyridin-3-amine;-   1-(4-(6-((4-(3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-3,5-difluorobenzyl)pyrrolidin-3-ol;-   1-(4-(6-((4-(3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-3,5-difluorobenzyl)pyrrolidine-3-carbonitrile;-   4-(3-amino-5-methylpiperidin-1-yl)-N-((6-(2,6-difluoro-4-((3-fluoropyrrolidin-1-yl)methyl)phenyl)-5-fluoropyridin-2-yl)methyl)pyridin-3-amine;-   3-amino-1-(3-{[(6-cyclohex-1-en-1-yl-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-4-ol;-   4-[3-amino-5-methylpiperidin-1-yl]-N-[(6-cyclohexyl-5-fluoropyridin-2-yl)methyl]pyridin-3-amine;-   3-amino-1-{3-[({6-[2,6-difluoro-4-(4-methoxytetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;-   4-[3-amino-5-methylpiperidin-1-yl]-N-({6-[2,6-difluoro-4-(4-methoxytetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)pyridin-3-amine;-   3-amino-1-{3-[({6-[2,6-difluoro-4-(4-fluorotetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;-   4-[3-amino-5-methylpiperidin-1-yl]-N-({6-[2,6-difluoro-4-(4-fluorotetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)pyridin-3-amine;-   3-amino-1-{3-[({6-[2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;-   4-[3-amino-5-methylpiperidin-1-yl]-N-({6-[2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)pyridin-3-amine;-   4-(3-amino-5-(trifluoromethyl)piperidin-1-yl)-N-((6-(2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl)-5-fluoropyridin-2-yl)methyl)pyridin-3-amine;-   4-[3-amino-5-methylcyclohexyl]-N-{[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}pyridin-3-amine;-   1-(4-{6-[({4-[3-amino-5-methylcyclohexyl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)cyclobutanol;-   4-[3-amino-5-methylcyclohexyl]-N-{[6-(2,6-difluoro-4-morpholin-4-ylphenyl)-5-fluoropyridin-2-yl]methyl}pyridin-3-amine;-   N-{[5-amino-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]methyl}-4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-amine;-   4-[3-amino-5-methylpiperidin-1-yl]-N-[(6-{2,6-difluoro-4-[3-fluoropyrrolidin-1-yl]phenyl}-5-fluoropyridin-2-yl)methyl]pyridin-3-amine;-   4-[3-amino-5-methylpiperidin-1-yl]-N-({6-[2,6-difluoro-4-(3-fluoropiperidin-1-yl)phenyl]-5-fluoropyridin-2-yl}methyl)pyridin-3-amine;-   1-(4-{6-[({4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)-3-methylazetidin-3-ol;-   3-amino-1-(3-{[(6-{2,6-difluoro-4-[tetrahydrofuran-3-yloxy]phenyl}-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-4-ol;-   4-[3-amino-5-methylpiperidin-1-yl]-N-[(6-{2,6-difluoro-4-[tetrahydrofuran-3-yloxy]phenyl}-5-fluoropyridin-2-yl)methyl]pyridin-3-amine;-   3-amino-1-{3-[({6-[2,6-difluoro-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;-   4-[3-amino-5-methylpiperidin-1-yl]-N-({6-[2,6-difluoro-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]-5-fluoropyridin-2-yl}methyl)pyridin-3-amine;-   4-[3-amino-5-methylpiperidin-1-yl]-N-[(6-{2,6-difluoro-4-[(1-methylpiperidin-4-yl)oxy]phenyl}-5-fluoropyridin-2-yl)methyl]pyridin-3-amine;-   3-amino-1-(3-{[(6-{4-[(3,3-difluorocyclobutyl)oxy]-2,6-difluorophenyl}-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-4-ol;-   4-[3-amino-5-methylpiperidin-1-yl]-N-[(6-{4-[(3,3-difluorocyclobutyl)oxy]-2,6-difluorophenyl}-5-fluoropyridin-2-yl)methyl]pyridin-3-amine;-   3-amino-1-[3-({[6-(2,6-difluoro-4-methoxyphenyl)-5-fluoropyridin-2-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-4-ol;-   4-[3-amino-5-methylpiperidin-1-yl]-N-{[6-(2,6-difluoro-4-methoxyphenyl)-5-fluoropyridin-2-yl]methyl}pyridin-3-amine;-   4-{6-[({4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3-fluorobenzonitrile;-   4-[3-amino-5-methylpiperidin-1-yl]-N-{[6-(1-benzothien-5-yl)-5-fluoropyridin-2-yl]methyl}pyridin-3-amine;-   6-{6-[({4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-1,3-dihydro-2H-indol-2-one;-   4-[3-amino-5-methylpiperidin-1-yl]-3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol;-   3-amino-1-[5-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}amino)-2,3-dihydrofuro[2,3-b]pyridin-4-yl]-5-methylpiperidin-4-ol;-   4-[3-amino-5-methylpiperidin-1-yl]-N-{[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}-6,7-dihydro-5H-cyclopenta[b]pyridin-3-amine;-   4-[3-amino-4-fluoropiperidin-1-yl]-N-{[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}pyridin-3-amine;-   4-[3-amino-5-methylpiperidin-1-yl]-N-{[7-(2,3-dihydro-1-benzofuran-6-yl)quinolin-2-yl]methyl}pyridin-3-amine;-   4-[3-amino-5-methylpiperidin-1-yl]-N-[(7-imidazo[1,2-a]pyridin-7-ylquinolin-2-yl)methyl]pyridin-3-amine;-   3-amino-1-(3-{[(7-imidazo[1,2-a]pyridin-7-ylquinolin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-4-ol;-   3-amino-1-{3-[({6-[2,6-difluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;-   3-amino-1-(3-{[(3-isopropylfuro[3,2-b]pyridin-5-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-4-ol;-   3-amino-1-(3-(((3-(2,6-difluoro-4-(hydroxymethyl)phenyl)furo[3,2-b]pyridin-5-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;-   3-amino-1-(3-(((3-(2-fluoro-4-(hydroxymethyl)phenyl)furo[3,2-b]pyridin-5-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;-   4-[3-amino-5-methylpiperidin-1-yl]-N-[(3-isopropylfuro[3,2-b]pyridin-5-yl)methyl]pyridin-3-amine;-   (4-(5-((4-(3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)furo[3,2-b]pyridin-3-yl)-3,5-difluorophenyl)methanol;-   (4-(5-((4-(3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)furo[3,2-b]pyridin-3-yl)-3-fluorophenyl)methanol;-   3-amino-1-(3-{[(3-cyclopropylfuro[3,2-b]pyridin-5-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-4-ol;-   4-[3-amino-5-methylpiperidin-1-yl]-N-[(3-cyclopropylfuro[3,2-b]pyridin-5-yl)methyl]pyridin-3-amine;-   1-(4-{6-[({4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenoxy)-2-methylpropan-2-ol;-   3-amino-1-{3-[({6-[2,6-difluoro-4-(2-hydroxy-2-methylpropoxy)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;-   2-(4-{6-[({4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)propan-2-ol;-   3-amino-1-{3-[({6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;-   4-{2-[({4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]quinolin-7-yl}-3-fluoro-1-methylpyridin-2(1H)-one;-   2-[({4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-6-(2,6-difluorophenyl)-5-fluoropyridin-3-amine;-   2-[({4-[3-amino-5-(trifluoromethyl)piperidin-1-yl]pyridin-3-yl}amino)methyl]-6-(2,6-difluorophenyl)-5-fluoropyridin-3-amine;-   4-[3-amino-5-methylpiperidin-1-yl]-N-{[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}-2-fluoropyridin-3-amine;    and-   4-[3-amino-5-methylpiperidin-1-yl]-N-{1-[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]ethyl}pyridin-3-amine.

Examples of the compounds of Formula (I) also include the followingcompounds and or pharmaceutically acceptable salts thereof:

-   (3R,4R,5S)-3-amino-1-{3-[({6-[2,6-difluoro-4-(3-hydroxytetrahydrofuran-3-yl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;-   (3R,4R,5S)-3-amino-1-(3-(((6-(2,6-difluoro-4-(1-hydroxycyclobutyl)phenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;-   (3R,4R,5S)-3-amino-1-(3-(((6-(2,6-difluoro-4-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;-   3-(4-{6-[({4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)tetrahydrofuran-3-ol;-   1-(4-(6-((4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-3,5-difluorophenyl)cyclobutanol;-   4-(4-(6-((4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-3,5-difluorophenyl)tetrahydro-2H-pyran-4-ol;-   1-(4-{6-[({4-[(3S,5R)-3-amino-5-(trifluoromethyl)piperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)cyclobutanol;-   (3R,4R,5S)-3-amino-1-{3-[({6-[2,6-difluoro-4-(1-hydroxycyclopropyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;-   (3R,4R,5S)-3-amino-1-(3-(((6-(2,6-difluoro-3-(1-hydroxycyclopropyl)phenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;-   1-(4-{6-[({4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)cyclopropanol;-   1-(3-(6-((4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-2,4-difluorophenyl)cyclopropanol;-   (3R,4R,5S)-3-amino-1-{3-[({6-[2,6-difluoro-4-(2-hydroxy-2-methylpropyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;-   1-(4-{6-[({4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)-2-methylpropan-2-ol;-   (3R,4R,5S)-3-amino-1-[3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-4-ol;-   (3R,4R,5S)-3-amino-1-(3-(((5-fluoro-6-(2-fluoro-6-methoxyphenyl)pyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;-   (3R,4R,5S)-3-amino-5-methyl-1-(3-(((3,3′,5′-trifluoro-[2,4′-bipyridin]-6-yl)methyl)amino)pyridin-4-yl)piperidin-4-ol;-   2-(6-((4-((3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-3-fluorobenzonitrile;-   (3R,4R,5S)-3-amino-1-(3-(((5-fluoro-6-(2-fluorophenyl)pyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;-   4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-{[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}pyridin-3-amine;-   4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)-N-((5-fluoro-6-(2-fluoro-6-methoxyphenyl)pyridin-2-yl)methyl)pyridin-3-amine;-   4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)-N-((3,3′,5′-trifluoro-2,4′-bipyridin-6-yl)methyl)pyridin-3-amine;-   2-(6-((4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-3-fluorobenzonitrile;-   4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)-N-((5-fluoro-6-(2-fluorophenyl)pyridin-2-yl)methyl)pyridin-3-amine;-   2-(4-{6-[({4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)-2-methylpropanenitrile;-   2-(4-{6-[({4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)-2-methylpropanenitrile;-   (3R,4R,5S)-3-amino-5-methyl-1-(3-{[(2′,6,6′-trifluorobiphenyl-3-yl)methyl]amino}pyridin-4-yl)piperidin-4-ol;-   4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-[(2′,6,6′-trifluorobiphenyl-3-yl)methyl]pyridin-3-amine;-   1-(5′-((4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-2,2′,6-trifluorobiphenyl-4-yl)cyclobutanol;-   4-(5′-((4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-2,2′,6-trifluorobiphenyl-4-yl)tetrahydro-2H-pyran-4-ol;-   (3R,4R,5S)-3-amino-1-[3-({[6-(2,6-difluorophenyl)pyridin-2-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-4-ol;-   4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-{[6-(2,6-difluorophenyl)pyridin-2-yl]methyl}pyridin-3-amine;-   (3R,4R,5S)-3-amino-1-[3-({[2-(2,6-difluorophenyl)pyrimidin-4-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-4-ol;-   4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-{[2-(2,6-difluorophenyl)pyrimidin-4-yl]methyl}pyridin-3-amine;-   (3R,4R,5S)-3-amino-1-(3-(((6-(2,6-difluoro-4-morpholinophenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;-   4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)-N-((6-(2,6-difluoro-4-morpholinophenyl)-5-fluoropyridin-2-yl)methyl)pyridin-3-amine;-   4-((3S,5R)-3-amino-5-(trifluoromethyl)piperidin-1-yl)-N-((6-(2,6-difluoro-4-morpholinophenyl)-5-fluoropyridin-2-yl)methyl)pyridin-3-amine;-   (3R,4R,5S)-3-amino-1-{3-[({6-[2,6-difluoro-4-(hydroxymethyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;-   (4-{6-[({4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)methanol;-   (3R,4R,5S)-3-amino-1-[3-({[6-(5,7-difluoroquinolin-6-yl)-5-fluoropyridin-2-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-4-ol;-   4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-{[6-(5,7-difluoroquinolin-6-yl)-5-fluoropyridin-2-yl]methyl}pyridin-3-amine;-   (3R,4R,5S)-3-amino-1-{3-[({6-[2,6-difluoro-4-(morpholin-4-ylmethyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;-   (3R,4R,5S)-3-amino-1-(3-(((6-(2,6-difluoro-4-((methylamino)methyl)phenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;-   (3R,4R,5S)-3-amino-1-(3-(((6-(4-(azetidin-1-ylmethyl)-2,6-difluorophenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;-   (3R,4R,5S)-3-amino-1-(3-(((6-(2,6-difluoro-4-(((R)-3-hydroxypyrrolidin-1-yl)methyl)phenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;-   (3R,4R,5S)-3-amino-1-(3-(((6-(2,6-difluoro-4-(((S)-3-hydroxypyrrolidin-1-yl)methyl)phenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;-   (R)-1-(4-(6-((4-((3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-3,5-difluorobenzyl)pyrrolidine-3-carbonitrile;-   (S)-1-(4-(6-((4-((3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-3,5-difluorobenzyl)pyrrolidine-3-carbonitrile;-   (3R,4R,5S)-3-amino-1-(3-(((6-(2,6-difluoro-4-(((R)-3-fluoropyrrolidin-1-yl)methyl)phenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;-   (3R,4R,5S)-3-amino-1-(3-(((6-(2,6-difluoro-4-(((S)-3-fluoropyrrolidin-1-yl)methyl)phenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;-   4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-({6-[2,6-difluoro-4-(morpholin-4-ylmethyl)phenyl]-5-fluoropyridin-2-yl}methyl)pyridin-3-amine;-   4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)-N-((6-(2,6-difluoro-4-((methylamino)methyl)phenyl)-5-fluoropyridin-2-yl)methyl)pyridin-3-amine;-   4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)-N-((6-(4-(azetidin-1-ylmethyl)-2,6-difluorophenyl)-5-fluoropyridin-2-yl)methyl)pyridin-3-amine;-   (R)-1-(4-(6-((4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-3,5-difluorobenzyl)pyrrolidin-3-ol;-   (S)-1-(4-(6-((4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-3,5-difluorobenzyl)pyrrolidin-3-ol;-   (R)-1-(4-(6-((4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-3,5-difluorobenzyl)pyrrolidine-3-carbonitrile;-   (S)-1-(4-(6-((4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-3,5-difluorobenzyl)pyrrolidine-3-carbonitrile;-   4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)-N-((6-(2,6-difluoro-4-(((R)-3-fluoropyrrolidin-1-yl)methyl)phenyl)-5-fluoropyridin-2-yl)methyl)pyridin-3-amine;-   4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)-N-((6-(2,6-difluoro-4-(((S)-3-fluoropyrrolidin-1-yl)methyl)phenyl)-5-fluoropyridin-2-yl)methyl)pyridin-3-amine;-   (3R,4R,5S)-3-amino-1-(3-{[(6-cyclohex-1-en-1-yl-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-4-ol;-   4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-[(6-cyclohexyl-5-fluoropyridin-2-yl)methyl]pyridin-3-amine;-   (3R,4R,5S)-3-amino-1-{3-[({6-[2,6-difluoro-4-(4-methoxytetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;-   4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-({6-[2,6-difluoro-4-(4-methoxytetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)pyridin-3-amine;-   (3R,4R,5S)-3-amino-1-{3-[({6-[2,6-difluoro-4-(4-fluorotetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;-   4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-({6-[2,6-difluoro-4-(4-fluorotetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)pyridin-3-amine;-   (3R,4R,5S)-3-amino-1-{3-[({6-[2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;-   4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-({6-[2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)pyridin-3-amine;-   4-((3S,5R)-3-amino-5-(trifluoromethyl)piperidin-1-yl)-N-((6-(2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl)-5-fluoropyridin-2-yl)methyl)pyridin-3-amine;-   4-[(1R,3S,5S)-3-amino-5-methylcyclohexyl]-N-{[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}pyridin-3-amine;-   1-(4-{6-[({4-[(1R,3S,5S)-3-amino-5-methylcyclohexyl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)cyclobutanol;-   4-[(1R,3S,5S)-3-amino-5-methylcyclohexyl]-N-{[6-(2,6-difluoro-4-morpholin-4-ylphenyl)-5-fluoropyridin-2-yl]methyl}pyridin-3-amine;-   N-{[5-amino-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]methyl}-4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-amine;-   4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-[(6-{2,6-difluoro-4-[(3R)-3-fluoropyrrolidin-1-yl]phenyl}-5-fluoropyridin-2-yl)methyl]pyridin-3-amine;-   4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-({6-[2,6-difluoro-4-(3-fluoropiperidin-1-yl)phenyl]-5-fluoropyridin-2-yl}methyl)pyridin-3-amine;-   1-(4-{6-[({4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)-3-methylazetidin-3-ol;-   (3R,4R,5S)-3-amino-1-(3-{[(6-{2,6-difluoro-4-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-4-ol;-   4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-[(6-{2,6-difluoro-4-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-5-fluoropyridin-2-yl)methyl]pyridin-3-amine;-   (3R,4R,5S)-3-amino-1-(3-{[(6-{2,6-difluoro-4-[(3S)-tetrahydrofuran-3-yloxy]phenyl}-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-4-ol;-   4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-[(6-{2,6-difluoro-4-[(3S)-tetrahydrofuran-3-yloxy]phenyl}-5-fluoropyridin-2-yl)methyl]pyridin-3-amine;-   (3R,4R,5S)-3-amino-1-{3-[({6-[2,6-difluoro-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;-   4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-({6-[2,6-difluoro-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]-5-fluoropyridin-2-yl}methyl)pyridin-3-amine;-   4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-[(6-{2,6-difluoro-4-[(1-methylpiperidin-4-yl)oxy]phenyl}-5-fluoropyridin-2-yl)methyl]pyridin-3-amine;-   (3R,4R,5S)-3-amino-1-(3-{[(6-{4-[(3,3-difluorocyclobutyl)oxy]-2,6-difluorophenyl}-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-4-ol;-   4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-[(6-{4-[(3,3-difluorocyclobutyl)oxy]-2,6-difluorophenyl}-5-fluoropyridin-2-yl)methyl]pyridin-3-amine;-   (3R,4R,5S)-3-amino-1-[3-({[6-(2,6-difluoro-4-methoxyphenyl)-5-fluoropyridin-2-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-4-ol;-   4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-{[6-(2,6-difluoro-4-methoxyphenyl)-5-fluoropyridin-2-yl]methyl}pyridin-3-amine;-   4-{6-[({4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3-fluorobenzonitrile;-   4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-{[6-(1-benzothien-5-yl)-5-fluoropyridin-2-yl]methyl}pyridin-3-amine;-   6-{6-[({4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-1,3-dihydro-2H-indol-2-one;-   (7R)-4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol;-   (3R,4R,5S)-3-amino-1-[5-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}amino)-2,3-dihydrofuro[2,3-b]pyridin-4-yl]-5-methylpiperidin-4-ol;-   4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-{[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}-6,7-dihydro-5H-cyclopenta[b]pyridin-3-amine;-   4-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-N-{[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}pyridin-3-amine;-   4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-{[7-(2,3-dihydro-1-benzofuran-6-yl)quinolin-2-yl]methyl}pyridin-3-amine;-   4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-[(7-imidazo[1,2-a]pyridin-7-ylquinolin-2-yl)methyl]pyridin-3-amine;-   (3R,4R,5S)-3-amino-1-(3-{[(7-imidazo[1,2-a]pyridin-7-ylquinolin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-4-ol;-   (3R,4R,5S)-3-amino-1-{3-[({6-[2,6-difluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;-   (3R,4R,5S)-3-amino-1-(3-{[(3-isopropylfuro[3,2-b]pyridin-5-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-4-ol;-   (3R,4R,5S)-3-amino-1-(3-(((3-(2,6-difluoro-4-(hydroxymethyl)phenyl)furo[3,2-b]pyridin-5-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;-   (3R,4R,5S)-3-amino-1-(3-(((3-(2-fluoro-4-(hydroxymethyl)phenyl)furo[3,2-b]pyridin-5-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;-   4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-[(3-isopropylfuro[3,2-b]pyridin-5-yl)methyl]pyridin-3-amine;-   (4-(5-((4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)furo[3,2-b]pyridin-3-yl)-3,5-difluorophenyl)methanol;-   (4-(5-((4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)furo[3,2-b]pyridin-3-yl)-3-fluorophenyl)methanol;-   (3R,4R,5S)-3-amino-1-(3-{[(3-cyclopropylfuro[3,2-b]pyridin-5-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-4-ol;-   4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-[(3-cyclopropylfuro[3,2-b]pyridin-5-yl)methyl]pyridin-3-amine;-   1-(4-{6-[({4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenoxy)-2-methylpropan-2-ol;-   (3R,4R,5S)-3-amino-1-{3-[({6-[2,6-difluoro-4-(2-hydroxy-2-methylpropoxy)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;-   2-(4-{6-[({4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)propan-2-ol;-   (3R,4R,5S)-3-amino-1-{3-[({6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;-   4-{2-[({4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]quinolin-7-yl}-3-fluoro-1-methylpyridin-2(1H)-one;-   2-[({4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-6-(2,6-difluorophenyl)-5-fluoropyridin-3-amine;-   2-[({4-[(3S,5R)-3-amino-5-(trifluoromethyl)piperidin-1-yl]pyridin-3-yl}amino)methyl]-6-(2,6-difluorophenyl)-5-fluoropyridin-3-amine;-   4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-{[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}-2-fluoropyridin-3-amine;    and-   4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-{1-[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]ethyl}pyridin-3-amine.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment (while theembodiments are intended to be combined as if written in multiplydependent form). Conversely, various features of the invention whichare, for brevity, described in the context of a single embodiment, canalso be provided separately or in any suitable subcombination. Thus, itis contemplated as features described as embodiments of the compounds ofFormula (I) can be combined in any suitable combination.

At various places in the present specification, certain features of thecompounds are disclosed in groups or in ranges. It is specificallyintended that such a disclosure include each and every individualsubcombination of the members of such groups and ranges. For example,the term “C₁₋₆ alkyl” is specifically intended to individually disclose(without limitation)methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl, and C₆alkyl.

The term “n-membered,” where n is an integer, typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

At various places in the present specification, variables definingdivalent linking groups may be described. It is specifically intendedthat each linking substituent include both the forward and backwardforms of the linking substituent. For example, —NR(CR′R″)_(n)— includesboth —NR(CR′R″)_(n)— and —(CR′R″)_(n)NR— and is intended to discloseeach of the forms individually. Where the structure requires a linkinggroup, the Markush variables listed for that group are understood to belinking groups. For example, if the structure requires a linking groupand the Markush group definition for that variable lists “alkyl” or“aryl” then it is understood that the “alkyl” or “aryl” represents alinking alkylene group or arylene group, respectively.

The term “substituted” means that an atom or group of atoms formallyreplaces hydrogen as a “substituent” attached to another group. The term“substituted”, unless otherwise indicated, refers to any level ofsubstitution, e.g., mono-, di-, tri-, tetra- or penta-substitution,where such substitution is permitted. The substituents are independentlyselected, and substitution may be at any chemically accessible position.It is to be understood that substitution at a given atom is limited byvalency. The phrase “optionally substituted” means unsubstituted orsubstituted. The term “substituted” means that a hydrogen atom isremoved and replaced by a substituent. A single divalent substituent,e.g., oxo, can replace two hydrogen atoms.

The term “C_(n-m)” indicates a range which includes the endpoints,wherein n and m are integers and indicate the number of carbons.Examples include C₁₋₄, C₁₋₆ and the like.

The term “alkyl” employed alone or in combination with other terms,refers to a saturated hydrocarbon group that may be straight-chain orbranched. The term “C_(n-m) alkyl”, refers to an alkyl group having n tom carbon atoms. An alkyl group formally corresponds to an alkane withone C—H bond replaced by the point of attachment of the alkyl group tothe remainder of the compound. In some embodiments, the alkyl groupcontains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3carbon atoms, or 1 to 2 carbon atoms. Examples of alkyl moietiesinclude, but are not limited to, chemical groups such as methyl, ethyl,n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higherhomologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl,1,2,2-trimethylpropyl and the like.

The term “alkenyl” employed alone or in combination with other terms,refers to a straight-chain or branched hydrocarbon group correspondingto an alkyl group having one or more double carbon-carbon bonds. Analkenyl group formally corresponds to an alkene with one C—H bondreplaced by the point of attachment of the alkenyl group to theremainder of the compound. The term “C_(n-m) alkenyl” refers to analkenyl group having n to m carbons. In some embodiments, the alkenylmoiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Example alkenylgroups include, but are not limited to, ethenyl, n-propenyl,isopropenyl, n-butenyl, sec-butenyl and the like.

The term “alkynyl” employed alone or in combination with other terms,refers to a straight-chain or branched hydrocarbon group correspondingto an alkyl group having one or more triple carbon-carbon bonds. Analkynyl group formally corresponds to an alkyne with one C—H bondreplaced by the point of attachment of the alkyl group to the remainderof the compound. The term “C_(n-m) alkynyl” refers to an alkynyl grouphaving n to m carbons. Example alkynyl groups include, but are notlimited to, ethynyl, propyn-1-yl, propyn-2-yl and the like. In someembodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3carbon atoms.

The term “alkylene”, employed alone or in combination with other terms,refers to a divalent alkyl linking group. An alkylene group formallycorresponds to an alkane with two C—H bond replaced by points ofattachment of the alkylene group to the remainder of the compound. Theterm “C_(n-m) alkylene” refers to an alkylene group having n to m carbonatoms. Examples of alkylene groups include, but are not limited to,ethan-1,2-diyl, propan-1,3-diyl, propan-1,2-diyl, butan-1,4-diyl,butan-1,3-diyl, butan-1,2-diyl, 2-methyl-propan-1,3-diyl and the like.

The term “alkoxy”, employed alone or in combination with other terms,refers to a group of formula —O-alkyl, wherein the alkyl group is asdefined above. The term “C_(n-m) alkoxy” refers to an alkoxy group, thealkyl group of which has n to m carbons. Example alkoxy groups includemethoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy andthe like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1to 3 carbon atoms.

The term “amino” refers to a group of formula —NH₂.

The term “carbamyl” refers to a group of formula —C(O)NH₂.

The term “carbonyl”, employed alone or in combination with other terms,refers to a —C(═O)— group, which also may be written as C(O).

The term “cyano” or “nitrile” refers to a group of Formula —C≡N, whichalso may be written as —CN.

The terms “halo” or “halogen”, used alone or in combination with otherterms, refers to fluoro, chloro, bromo and iodo. In some embodiments,“halo” refers to a halogen atom selected from F, Cl, or Br. In someembodiments, halo is F.

The term “haloalkyl” as used herein refers to an alkyl group in whichone or more of the hydrogen atoms has been replaced by a halogen atom.The term “C_(n-m) haloalkyl” refers to a C_(n-m) alkyl group having n tom carbon atoms and from at least one up to {2(n to m)+1}halogen atoms,which may either be the same or different. In some embodiments, thehalogen atoms are fluoro atoms. In some embodiments, the haloalkyl grouphas 1 to 6 or 1 to 4 carbon atoms. Example haloalkyl groups include CF₃,C₂F₅, CHF₂, CCl₃, CHCl₂, C₂Cl₅ and the like. In some embodiments, thehaloalkyl group is a fluoroalkyl group.

The term “haloalkoxy”, employed alone or in combination with otherterms, refers to a group of Formula —O-haloalkyl, wherein the haloalkylgroup is as defined above. The term “C_(n-m) haloalkoxy” refers to ahaloalkoxy group, the haloalkyl group of which has n to m carbons.

Example haloalkoxy groups include trifluoromethoxy and the like. In someembodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

The term “oxo” refers to an oxygen atom as a divalent substituent,forming a carbonyl group when attached to carbon, or attached to aheteroatom forming a sulfoxide or sulfone group, or an N-oxide group.

The term “sulfido” refers to a sulfur atom as a divalent substituent,forming a thiocarbonyl group (C═S) when attached to carbon.

The term “aromatic” refers to a carbocycle or heterocycle having one ormore polyunsaturated rings having aromatic character (i.e., having(4n+2) delocalized π (pi) electrons where n is an integer).

The term “aryl,” employed alone or in combination with other terms,refers to an aromatic hydrocarbon group, which may be monocyclic orpolycyclic (e.g., having 2, 3 or 4 fused rings). The term “C_(n-m) aryl”refers to an aryl group having from n to m ring carbon atoms.

Aryl groups include, e.g., phenyl, naphthyl, anthracenyl, phenanthrenyl,indanyl, indenyl and the like. In some embodiments, aryl groups havefrom 6 to about 20 carbon atoms, from 6 to about 15 carbon atoms, orfrom 6 to about 10 carbon atoms. In some embodiments, the aryl group isphenyl.

The term “arylalkyl,” employed alone or in combination with other terms,refers to a group of formula -alkylene-aryl. In some embodiments,arylalkyl is C₆₋₁₀ aryl-C₁₋₃ alkyl. In some embodiments, arylalkyl isC₆₋₁₀ aryl-C₁₋₄ alkyl. In some embodiments, arylalkyl is benzyl.

The term “heteroaryl” or “heteroaromatic,” employed alone or incombination with other terms, refers to a monocyclic or polycyclicaromatic heterocycle having at least one heteroatom ring member selectedfrom sulfur, oxygen and nitrogen. In some embodiments, the heteroarylring has 1, 2, 3 or 4 heteroatom ring members independently selectedfrom nitrogen, sulfur and oxygen. In some embodiments, any ring-formingN in a heteroaryl moiety can be an N-oxide. In some embodiments, theheteroaryl has 5-10 ring atoms including carbon atoms and 1, 2, 3 or 4heteroatom ring members independently selected from nitrogen, sulfur andoxygen. In some embodiments, the heteroaryl has 5-6 ring atoms and 1 or2 heteroatom ring members independently selected from nitrogen, sulfurand oxygen. In some embodiments, the heteroaryl is a five-membered orsix-membered heteroaryl ring. In other embodiments, the heteroaryl is aneight-membered, nine-membered or ten-membered fused bicyclic heteroarylring. Example heteroaryl groups include, but are not limited to,pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl,azolyl, oxazolyl, thiazolyl, imidazolyl, furanyl, thiophenyl,quinolinyl, isoquinolinyl, naphthyridinyl (including 1,2-, 1,3-, 1,4-,1,5-, 1,6-, 1,7-, 1,8-, 2,3- and 2,6-naphthyridinyl), indolyl,benzothiophenyl, benzofuranyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl,purinyl, or the like.

A five-membered heteroaryl ring is a heteroaryl group having five ringatoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independentlyselected from N, O and S. Exemplary five-membered ring heteroarylsinclude thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl,pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl,1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl,1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.

A six-membered heteroaryl ring is a heteroaryl group having six ringatoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independentlyselected from N, O and S. Exemplary six-membered ring heteroaryls arepyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.

The term “heteroarylalkyl,” employed alone or in combination with otherterms, refers to a group of formula -alkylene-heteroaryl. In someembodiments, heteroarylalkyl is C₁₋₉ heteroaryl-C₁₋₃ alkyl, wherein theheteroaryl portion is monocyclic or bicyclic and has 1, 2, 3, or 4heteroatom ring members independently selected from nitrogen, sulfur andoxygen. In some embodiments, heteroarylalkyl is C₁₋₉ heteroaryl-C₁₋₄alkyl, wherein the heteroaryl portion is monocyclic or bicyclic and has1, 2, 3, or 4 heteroatom ring members independently selected fromnitrogen, sulfur and oxygen.

The term “cycloalkyl,” employed alone or in combination with otherterms, refers to a non-aromatic, saturated, monocyclic, bicyclic orpolycyclic hydrocarbon ring system, including cyclized alkyl and alkenylgroups. The term “C_(n-m) cycloalkyl” refers to a cycloalkyl that has nto m ring member carbon atoms. Cycloalkyl groups can include mono- orpolycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles.Cycloalkyl groups can have 3, 4, 5, 6 or 7 ring-forming carbons (C₃-7).In some embodiments, the cycloalkyl group has 3 to 6 ring members, 3 to5 ring members, or 3 to 4 ring members. In some embodiments, thecycloalkyl group is monocyclic. In some embodiments, the cycloalkylgroup is monocyclic or bicyclic. In some embodiments, the cycloalkylgroup is a C₃₋₆ monocyclic cycloalkyl group. Ring-forming carbon atomsof a cycloalkyl group can be optionally oxidized to form an oxo orsulfido group. Cycloalkyl groups also include cycloalkylidenes. In someembodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl. Also included in the definition of cycloalkyl are moietiesthat have one or more aromatic rings fused (i.e., having a bond incommon with) to the cycloalkyl ring, e.g., benzo or thienyl derivativesof cyclopentane, cyclohexane and the like. A cycloalkyl group containinga fused aromatic ring can be attached through any ring-forming atomincluding a ring-forming atom of the fused aromatic ring. Examples ofcycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl,cycloheptatrienyl, norbornyl, norpinyl, norcarnyl,bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, and the like. In someembodiments, the cycloalkyl group is cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl.

The term “cycloalkylalkyl,” employed alone or in combination with otherterms, refers to a group of formula -alkylene-cycloalkyl. In someembodiments, cycloalkylalkyl is C₃₋₇ cycloalkyl-C₁₋₃ alkyl, wherein thecycloalkyl portion is monocyclic or bicyclic. In some embodiments,cycloalkylalkyl is C₃₋₇ cycloalkyl-C₁₋₄ alkyl, wherein the cycloalkylportion is monocyclic or bicyclic.

The term “heterocycloalkyl”, employed alone or in combination with otherterms, refers to non-aromatic ring or ring system, which may optionallycontain one or more alkenylene groups as part of the ring structure,which has at least one heteroatom ring member independently selectedfrom nitrogen, sulfur oxygen and phosphorus, and which has 4-12 ringmembers, 4-10 ring members, 4-7 ring members or 4-6 ring members.Included in heterocycloalkyl are monocyclic 4-, 5-, 6- and 7-memberedheterocycloalkyl groups. Heterocycloalkyl groups can include mono- orbicyclic (e.g., having two fused or bridged rings) ring systems. In someembodiments, the heterocycloalkyl group is a monocyclic group having 1,2 or 3 heteroatoms independently selected from nitrogen, sulfur andoxygen. Ring-forming carbon atoms and heteroatoms of a heterocycloalkylgroup can be optionally oxidized to form an oxo or sulfide group orother oxidized linkage (e.g., C(O), S(O), C(S) or S(O)₂, N-oxide etc.)or a nitrogen atom can be quaternized. The heterocycloalkyl group can beattached through a ring-forming carbon atom or a ring-formingheteroatom. In some embodiments, the heterocycloalkyl group contains 0to 3 double bonds. In some embodiments, the heterocycloalkyl groupcontains 0 to 2 double bonds. Also included in the definition ofheterocycloalkyl are moieties that have one or more aromatic rings fused(i.e., having a bond in common with) to the heterocycloalkyl ring, e.g.,benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. Aheterocycloalkyl group containing a fused aromatic ring can be attachedthrough any ring-forming atom including a ring-forming atom of the fusedaromatic ring. Examples of heterocycloalkyl groups include azetidine,azepane, dihydrobenzofuran, dihydrofuran, dihydropyran, morpholine,3-oxa-9-azaspiro[5.5]undecane, 1-oxa-8-azaspiro[4.5]decane, piperidine,piperazine, pyran, pyrrolidine, quinuclidine, tetrahydrofuran,tetrahydropyran, 1,2,3,4-tetrahydroquinoline, tropane, andthiomorpholine.

As used herein, the term “heterocycloalkylalkyl,” employed alone or incombination with other terms, refers to a group of formula-alkylene-heterocycloalkyl. In some embodiments, heterocycloalkylalkylis C₂₋₉ heterocycloalkyl-C₁₋₃ alkyl, wherein the heterocycloalkylportion is monocyclic or bicyclic and has 1, 2, 3, or 4 heteroatom ringmembers independently selected from nitrogen, sulfur and oxygen. In someembodiments, heterocycloalkylalkyl is C₂₋₉ heterocycloalkyl-C₁₋₄ alkyl,wherein the heterocycloalkyl portion is monocyclic or bicyclic and has1, 2, 3, or 4 heteroatom ring members independently selected fromnitrogen, sulfur and oxygen.

For the terms “e.g.” and “such as,” and grammatical equivalents thereof,the phrase “and without limitation” is understood to follow unlessexplicitly stated otherwise.

As used herein, the singular forms “a,” “an,” and “the” include pluralreferents unless the context clearly dictates otherwise.

As used herein, the term “about” means “approximately” (e.g., plus orminus approximately 10% of the indicated value).

At certain places, the definitions or embodiments refer to specificrings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwiseindicated, these rings can be attached to any ring member provided thatthe valency of the atom is not exceeded. For example, an azetidine ringmay be attached at any position of the ring, whereas an azetidin-3-ylring is attached at the 3-position.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present invention are described and may be isolated asa mixture of isomers or as separated isomeric forms.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. One method includes fractionalrecrystallization using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, e.g., optically active acids,such as the D and L forms of tartaric acid, diacetyltartaric acid,dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or thevarious optically active camphorsulfonic acids such as β-camphorsulfonicacid. Other resolving agents suitable for fractional crystallizationmethods include stereoisomerically pure forms of a-methylbenzylamine(e.g., S and R forms, or diastereomerically pure forms),2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

In some embodiments, the compounds of the invention have the(R)-configuration. In other embodiments, the compounds have the(S)-configuration. In compounds with more than one chiral centers, eachof the chiral centers in the compound may be independently (R) or (S),unless otherwise indicated.

Compounds of the invention also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical Formula and total charge. Exampleprototropic tautomers include ketone—enol pairs, amide—imidic acidpairs, lactam—lactim pairs, enamine-imine pairs, and annular forms wherea proton can occupy two or more positions of a heterocyclic system,e.g., 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole and 1H- and 2H-pyrazole. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium.

The term, “compound,” as used herein is meant to include allstereoisomers, geometric isomers, tautomers and isotopes of thestructures depicted.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.,hydrates and solvates) or can be isolated. When in the solid state, thecompounds described herein and salts thereof may occur in various formsand may, e.g., take the form of solvates, including hydrates. Thecompounds may be in any solid state form, such as a polymorph orsolvate, so unless clearly indicated otherwise, reference in thespecification to compounds and salts thereof should be understood asencompassing any solid state form of the compound.

In some embodiments, the compounds of the invention, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, e.g., a composition enriched in the compounds of the invention.Substantial separation can include compositions containing at leastabout 50%, at least about 60%, at least about 70%, at least about 80%,at least about 90%, at least about 95%, at least about 97%, or at leastabout 99% by weight of the compounds of the invention, or salt thereof.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The expressions, “ambient temperature” and “room temperature,” as usedherein, are understood in the art, and refer generally to a temperature,e.g., a reaction temperature, that is about the temperature of the roomin which the reaction is carried out, e.g., a temperature from about 20°C. to about 30° C.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. The term “pharmaceutically acceptablesalts” refers to derivatives of the disclosed compounds wherein theparent compound is modified by converting an existing acid or basemoiety to its salt form. Examples of pharmaceutically acceptable saltsinclude, but are not limited to, mineral or organic acid salts of basicresidues such as amines; alkali or organic salts of acidic residues suchas carboxylic acids; and the like. The pharmaceutically acceptable saltsof the present invention include the non-toxic salts of the parentcompound formed, e.g., from non-toxic inorganic or organic acids. Thepharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, alcohols (e.g., methanol, ethanol,iso-propanol or butanol) or acetonitrile (MeCN) are preferred. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences, 17^(th)Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J.Pharm. Sci., 1977, 66(1), 1-19 and in Stahl et al., Handbook ofPharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002). Insome embodiments, the compounds described herein include the N-oxideforms.

The following abbreviations may be used herein: AcOH (acetic acid); aq.(aqueous); atm. (atmosphere(s)); Boc (t-butoxycarbonyl); BOP((benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate); Br₂ (bromine); Cbz (carboxybenzyl); calc.(calculated); CeCl₃.7H₂O (cerium (III) chloride heptahydrate); CuI(copper (I) iodide); d (doublet); dd (doublet of doublets); DCM(dichloromethane); DIAD (N,N′-diisopropyl azidodicarboxylate); DIC(N,N′-diisopropylcarbodiimide); DIPEA (N,N-diisopropylethylamine); DMAP(4-dimethylaminopyridine); DMF (N,N-dimethylformamide); Et (ethyl); Et₂O(diethyl ether); EtOAc (ethyl acetate); EtOH (ethanol); Fmoc(9-fluorenylmethylmethoxycarbonyl); g (gram(s)); h (hour(s)); H₂(hydrogen gas); HATU(N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate); HCl (hydrochloric acid/hydrogen choride); HPLC(high performance liquid chromatography); H₂SO₄ (sulfuric acid); Hz(hertz); I₂ (iodine); IPA (isopropyl alcohol); J (coupling constant);KOH (potassium hydroxide); K₃PO₄ (potassium phosphate); K₃PO₄.H₂O(tripotassium phosphate hydrate); LiHMDS (lithium hexamethyldisilazide);LCMS (liquid chromatography—mass spectrometry); LiAlH₄ (lithiumtetrahydroaluminate); LiBH₄ (lithium tetrahydroborate); LiOH (lithiumhydroxide); m (multiplet); M (molar); MeI (methyl iodide); MS (Massspectrometry); Me (methyl); MeCN (acetonitrile); MeOH (methanol); mg(milligram(s)); min. (minutes(s)); mL (milliliter(s)); mmol(millimole(s)); MnO₂ (manganese (IV) oxide); MoSO₄ (molybdenum sulfate);N (normal); NaBH₄ (sodium tetrahydroborate); Na₂Co₃ (sodium carbonate);NH₃ (ammonia); NaHCO₃ (sodium bicarbonate); NaOH (sodium hydroxide);Na₂S (sodium sulfide); Na₂SO₄ (sodium sulfate); Na₂S₂O₃ (sodiumthiosulfate); NH₄OH (ammonium hydroxide); nM (nanomolar); NMR (nuclearmagnetic resonance spectroscopy); Pd (palladium); Pd(OAc)₂ (palladiumacetate); pM (picomolar); PPh₃ (triphenylphosphine); RP-HPLC (reversephase high performance liquid chromatography); t (triplet or tertiary);t-Bu (tert-butyl); TEA (triethylamine); TFA (trifluoroacetic acid); THF(tetrahydrofuran); TiCl₄ (titanium tetrachloride); TLC (thin layerchromatography); μg (microgram(s)); L (microliter(s)); M (micromolar);wt % (weight percent).

II. Synthesis

Compounds of the invention, including salts thereof, can be preparedusing known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes, such as those inthe Schemes below.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), the intermediatesor products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups is described, e.g., in Kocienski, Protecting Groups,(Thieme, 2007); Robertson, Protecting Group Chemistry, (OxfordUniversity Press, 2000); Smith et al., March's Advanced OrganicChemistry: Reactions, Mechanisms, and Structure, 6^(th) Ed. (Wiley,2007); Peturssion et al., “Protecting Groups in Carbohydrate Chemistry,”J. Chem. Educ., 1997, 74(11), 1297; and Wuts et al., Protective Groupsin Organic Synthesis, 4th Ed., (Wiley, 2006).

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), massspectrometry or by chromatographic methods such as high performanceliquid chromatography (HPLC) or thin layer chromatography (TLC).

The Schemes below provide general guidance in connection with preparingthe compounds of the invention. One skilled in the art would understandthat the preparations shown in the Schemes can be modified or optimizedusing general knowledge of organic chemistry to prepare variouscompounds of the invention.

A general syntheses of compounds of Formula (I) is shown in Scheme 1.Suzuki, Buchwald or Stille coupling of compound 1-1 (Lv=Cl, Br, I)results in the formation of the compound 1-2. Reduction of the ester toalcohol followed by oxidation of the resulting alcohol moiety toaldehyde leads to compound 1-3. Reductive amination of aldehyde 1-3 witha desired amine 1-4 followed by global deprotection of the protectivegroups results in the formation of the compounds of formula 1-5.

Alternatively, compounds of formula 1-5 can be synthesized according toScheme 2. Reduction of the ester 2-1 to an alcohol followed by oxidationof the resulting alcohol moiety to aldehyde leads to compound 2-2.Reductive amination of the obtained aldehyde with the amine 1-4 givesthe compound 2-3. Suzuki, Buchwald or Stille coupling of the compound2-3 followed by global deprotection of the protective groups results inthe formation of the compounds of formula 1-5. To provide forselectivity, the amine attached to the piperidine or cyclohexyl ring ofcompound 1-4 can be protected for the reductive amination reaction(e.g., with a carbamate protecting group such as BOC).

Amine compounds 3-5 (wherein X═N) can be prepared as shown in Scheme 3.A suitably substituted 4-chloro-3-nitropyridine 3-1 can react with asuitably substituted piperidine 3-2 in the presence of a suitable baseor an organometallic catalyst to give compounds of formula 3-4.Reduction of the nitro group, e.g., in the presence of iron in aceticacid, provides amine 3-5 (X═N). Cyclohexyl analogues (compounds offormula 3-3 wherein X═CH) can be prepared by analogous by organometalliccross-coupling, e.g., with a compound of formula 3-3 followed byreduction of the olefinic C═C bond. To provide for selectivity, theamine attached to the piperidine or cyclohexyl ring of compound 3-2 or3-3 can be protected for the cross-coupling reaction (e.g., with acarbamate protecting group such as BOC) which would provide compound 3-5in suitable protected form for a selective reductive amination reactionas described above.

The compounds Formula (I) where A is furopyridine can be prepared asillustrated in Scheme 4. Esterification of 5-hydroxypicolinic acid 4-1can be performed in methanol in the presence of catalytic amount ofconcentrated sulfuric acid. Iodination of the resulted ester 4-2 yieldscompound 4-3. Sonogashira coupling then leads to the formation of thefuran ring in the compound 4-4. TMS removal by potassium carbonate inmethanol affords compound 4-5. Bromination of the double bond followedby treatment of the resulting product 4-6 with base gives the compound4-7. Reduction of the acid to alcohol followed by oxidation of theresultant alcohol moiety to aldehyde leads to compound 4-8. Reductiveamination of the aldehyde 4-8 with a desired amine gives the compound4-9. Bromo-compound 4-9 can then be subjected to Suzuki coupling withdesired boronic acid or ester (or another functional groupinterconversion) to provide compounds 4-10 wherein R can be variousgroups. In cases where alkenyl boronic esters are used for the Suzukicoupling, an extra step of the reduction of the double bond is performedvia catalytic hydrogenation. Finally, global deprotection of theprotective groups results in the formation of the compounds of formula4-10.

Starting materials, reagents and intermediates whose synthesis is notdescribed herein are either commercially available, known in theliterature, or may be prepared by methods known to one skilled in theart.

It will be appreciated by one skilled in the art that the processesdescribed are not the exclusive means by which compounds of theinvention may be synthesized and that a broad repertoire of syntheticorganic reactions is available to be potentially employed insynthesizing compounds of the invention. The person skilled in the artknows how to select and implement appropriate synthetic routes. Suitablesynthetic methods of starting materials, intermediates and products maybe identified by reference to the literature, including referencesources such as: Advances in Heterocyclic Chemistry, Vols. 1-107(Elsevier, 1963-2012); Journal of Heterocyclic Chemistry Vols. 1-49(Journal of Heterocyclic Chemistry, 1964-2012); Carreira, et al. (Ed.)Science of Synthesis, Vols. 1-48 (2001-2010) and Knowledge UpdatesKU2010/1-4; 2011/1-4; 2012/1-2 (Thieme, 2001-2012); Katritzky, et al.(Ed.) Comprehensive Organic Functional Group Transformations, (PergamonPress, 1996); Katritzky et al. (Ed.); Comprehensive Organic FunctionalGroup Transformations II (Elsevier, 2^(nd) Edition, 2004); Katritzky etal. (Ed.), Comprehensive Heterocyclic Chemistry (Pergamon Press, 1984);Katritzky et al., Comprehensive Heterocyclic Chemistry II, (PergamonPress, 1996); Smith et al., March's Advanced Organic Chemistry:Reactions, Mechanisms, and Structure, 6^(th) Ed. (Wiley, 2007); Trost etal. (Ed.), Comprehensive Organic Synthesis (Pergamon Press, 1991).

III. Uses of the Compounds

Compounds of the invention can inhibit the activity of one or moremembers of the Pim kinase family and, thus, are useful in treatingdiseases and disorders associated with activity of Pim kinases. For theuses described herein, any of the compounds of the invention, includingany of the embodiments thereof, may be used.

The compounds of the invention can inhibit one or more of Pim1, Pim2 andPim3. In some embodiments the compounds are selective for one Pim kinaseover another. “Selective” means that the compound binds to or inhibits aPim kinase with greater affinity or potency, respectively, compared to areference enzyme, such as another Pim kinase. For example, the compoundscan be selective for Pim1 over Pim2 and Pim3, selective for Pim2 overPim1 and Pim3, or selective for Pim3 over Pim1 and Pim2. In someembodiments, the compounds inhibit all of the Pim family members (e.g.,Pim1, Pim2 and Pim3). In some embodiments, the compounds can beselective for Pim over other kinases such as receptor and non-receptorSer/Thr kinases such as Akt1, Akt2, Akt3, TGF-βR, PKA, PKG, PKC,CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK and mTOR; receptor Tyrkinases such as EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFαR,PDGFβR, CSFIR, KIT, FLK-II, KDR/FLK-1, FLK-4, fit-1, FGFR1, FGFR2,FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR/Flt2, Flt4,EphA1, EphA2, EphA3, EphB2, EphB4, Tie2; and non-receptor Tyr kinasessuch as Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK or ABL. In general,selectivity can be at least about 5-fold, at least about 10-fold, atleast about 20-fold, at least about 50-fold, at least about 100-fold, atleast about 200-fold, at least about 500-fold or at least about1000-fold. The method of inhibiting a Pim1, Pim2 or Pim3 kinase includescontacting the appropriate enzyme with the compound of the invention, orany of the embodiments thereof, or a pharmaceutically acceptable saltthereof.

Thus, the present disclosure provides methods of treating a Pimkinase-associated disease or disorder in an individual (e.g., patient)by administering to the individual in need of such treatment atherapeutically effective amount or dose of a compound of the invention,or any of the embodiments thereof, or a pharmaceutical compositionthereof. The present disclosure also provides a compound of theinvention, or any of the embodiments thereof, or a pharmaceuticalcomposition thereof, for use in treating a Pim kinase-associated diseaseor disorder. Also provided is the use of a compound of the invention, orany of the embodiments thereof, or a pharmaceutical composition thereof,in the manufacture of a medicament for treating a Pim kinase-associateddisease or disorder.

A Pim kinase-associated disease can include any disease, disorder orcondition that is directly or indirectly linked to expression oractivity of the Pim kinase, including over-expression and/or abnormalactivity levels. Abnormal activity levels can be determined by comparingactivity level in normal, healthy tissue or cells with activity level indiseased cells. A Pim kinase-associated disease can also include anydisease, disorder or condition that can be prevented, ameliorated,inhibited or cured by modulating Pim kinase activity. In someembodiments, the disease is characterized by the abnormal activity orexpression (e.g., overexpression) of one or more Pim1, Pim2 and Pim3. Insome embodiments, the disease is characterized by mutant Pim1, Pim2 orPim3. A Pim kinase associated disease can also refer to any disease,disorder or condition wherein modulating the expression or activity ofone or more Pim kinases is beneficial.

Pim kinase associated diseases that can be treated using the compoundsof the invention include cancer, including, in particular, cancers inwhich Pim kinases are upregulated or an oncogene, e.g., Myc or Bcl2, isactivated. Pim kinase associated diseases include solid tumors, e.g.,prostate cancer, colon cancer, esophageal cancer, endometrial cancer,ovarian cancer, uterine cancer, renal cancer, hepatic cancer, pancreaticcancer, gastric cancer, breast cancer, lung cancer, cancers of the heador neck, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc. Pimkinase associated diseases also include hematological cancers, e.g.,lymphoma, leukemia such as acute lymphoblastic leukemia (ALL), acutemyelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), chronicmyelogenous leukemia (CML), diffuse large B-cell lymphoma (DLBCL),mantle cell lymphoma, non-Hodgkin lymphoma (including relapsednon-Hodgkin lymphoma, refractory non-Hodgkin lymphoma and recurrentfollicular non-Hodgkin lymphoma), Hodgkin lymphoma and multiple myeloma.

Pim kinase associated diseases that can be treated using the compoundsof the invention also include myeloproliferative disorders such aspolycythemia vera (PV), essential thrombocythemia (ET), chronicmyelogenous leukemia (CML) and the like. The myeloproliferative disordercan be myelofibrosis such as primary myelofibrosis (PMF),post-polycythemia vera/essential thrombocythemia myelofibrosis(Post-PV/ET MF), post-essential thrombocythemia myelofibrosis (Post-ETMF) or post-polycythemia vera myelofibrosis (Post-PV MF).

Pim kinase associated diseases that can be treated using the compoundsof the invention also include myelodysplastic syndrome, includingrefractory anemia (RA), refractory cytopenia with unilineage dysplasia(refractory anemia, Refractory neutropenia, and Refractorythrombocytopenia), refactory anemia with ringed sideroblasts (RARS),refractory anemia with ring sideroblasts—thrombocytosis (RARS-t),Refractory cytopenia with multilineage dysplasia (RCMD), refactoryanemia with excess blasts (RAEB) (including refactory anemia with excessblasts-I (RAEB-I) and refactory anemia with excess blasts-II (RAEB-II),refactory anemia with excess blasts in transformation (RAEB-t),5q-syndrome, myelodysplasia unclassifiable refractory cytopenia ofchildhood and chronic myelomonocytic leukemia (CMML).

Pim kinase-associated diseases that can be treated using the compoundsof the invention also include myelodysplastic/myeloproliferativediseases. Myelodysplastic/myeloproliferative diseases include myeloiddisorders that have both dysplastic and proliferative features, such aschronic myelomonocytic leukemia (CMML), atypical chronic myeloidleukemia, juvenile myelomonocytic leukemia, and unclassifiablemyelodysplastic/myeloproliferative disease.

Pim kinase-associated diseases that can be treated with compoundsaccording to the invention also include immune disorders such asautoimmune diseases. The immune disorders include multiple sclerosis,rheumatoid arthritis, allergy, food allergy, asthma, lupus, inflammatorybowel disease and ulcerative colitis.

Pim kinase-associated diseases that can be treated with compoundsaccording to the invention also include atherosclerosis.

The compounds of the invention can also be used to inhibit diseaseprocesses in which Pim-kinases are involved, including angiogenesis andtumor metastasis.

Due to the fact that Pim kinases are regulated by the JAK/STAT pathway,the compounds of the invention are useful to treat diseases in whichmodulating JAK/STAT signaling is beneficial. Thus, other diseases thatcan be treated using the compounds of the invention include Crohn'sdisease, irritable bowel syndrome, pancreatitis, diverticulosis, Grave'sdisease, juvenile rheumatoid arthritis, osteoarthritis, psoriaticarthritis, ankylosing spondylitis, myasthenia gravis, vasculitis,autoimmune thyroiditis, dermatitis, psoriasis, scleroderma, systemicsclerosis, vitiligo, graft versus host disease, Sjogren's syndrome,glomerulonephritis and diabetes mellitis (type I).

The terms “individual” or “patient,” used interchangeably, refer to anyanimal, including mammals, preferably mice, rats, other rodents,rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and mostpreferably humans.

The phrase “therapeutically effective amount” refers to the amount ofactive compound or pharmaceutical agent that elicits the biological ormedicinal response in a tissue, system, animal, individual or human thatis being sought by a researcher, veterinarian, medical doctor or otherclinician.

As used herein, the term “treating” or “treatment” refers to one or moreof (1) inhibiting the disease; e.g., inhibiting a disease, condition ordisorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology);and (2) ameliorating the disease; e.g., ameliorating a disease,condition or disorder in an individual who is experiencing or displayingthe pathology or symptomatology of the disease, condition or disorder(i.e., reversing the pathology and/or symptomatology) such as decreasingthe severity of disease. In one embodiment, treating or treatmentincludes preventing or reducing the risk of developing the disease;e.g., preventing or reducing the risk of developing a disease, conditionor disorder in an individual who may be predisposed to the disease,condition or disorder but does not yet experience or display thepathology or symptomatology of the disease.

Combination Therapies

Cancer cell growth and survival can be impacted by multiple signalingpathways. Thus, it is useful to combine different kinase inhibitors,exhibiting different preferences in the kinases which they modulate theactivities of, to treat such conditions. Targeting more than onesignaling pathway (or more than one biological molecule involved in agiven signaling pathway) may reduce the likelihood of drug-resistancearising in a cell population, and/or reduce the toxicity of treatment.

Accordingly, the Pim inhibitors of the present invention can be used incombination with one or more other kinase inhibitors for the treatmentof diseases, such as cancer, that are impacted by multiple signalingpathways. For example, the compounds of the invention can be combinedwith one or more inhibitors of the following kinases for the treatmentof cancer: Akt1, Akt2, Akt3, TGF-βR, PKA, PKG, PKC, CaM-kinase,phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4,INS-R, IGF-1R, IR-R, PDGFαR, PDGFβR, CSFIR, KIT, FLK-II, KDR/FLK-1,FLK-4, fit-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB,TRKC, FLT3, VEGFR/Flt2, Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2,Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK and B-Raf.Additionally, the Pim inhibitors of the invention can be combined withinhibitors of kinases associated with the PIK3/Akt/mTOR signalingpathway, such as PI3K, Akt (including Akt1, Akt2 and Akt3) and mTORkinases.

The Pim inhibitors of the present invention can be used in combinationwith one or more other BET bromodomain inhibitors such a BRD2, BRD3,BRD4 and BRDT that are useful for the treatment of diseases, such ascancer.

In some embodiments Pim inhibitors of the invention can be combined withinhibitors selective for JAK1 and/or JAK2 (e.g., ruxolitinib,baricitinib, momelotinib, filgotinib, pacritinib, INCB039110,INCB052793, INCB054707, CYT387, ABT494, AZD1480, XL019, CEP-33779, AZ960, TG101209, and gandotinib). In some embodiments Pim inhibitors ofthe invention can be combined with inhibitors selective for JAK1 (e.g.INCB039110, INCB052793, INCB054707, and ABT494) such as those disclosedin e.g., WO 2010/135650, WO 2011/028685, WO 2011/112662, WO 2012/068450,WO 2012/068440, WO 2012/177606, WO 2013/036611, WO 2013/026025, WO2014/138168, WO 2013/173720, WO 2015/021153, WO 2014/071031, WO2014/106706, WO 2015/131031, WO 2015/168246, and WO 2015/184305. In someembodiments Pim inhibitors of the invention can be combined withinhibitors selective for JAK2 (e.g., pacritinib, AZD1480, XL019,CEP-33779, AZ 960, TG101209, and gandotinib).

In some embodiments Pim inhibitors of the invention can be combined withinhibitors selective for PI3K delta (e.g., idelalisib, INCB040093,INCB050465, and TGR 1202) such as those disclosed in e.g., WO2011/0008487, WO 2011/075643, WO 2011/075630, WO 2011/163195, WO2011/130342, WO 2012/087881, WO 2012/125629, WO 2012/135009, WO2013/033569, WO2013/151930, WO 2014/134426, WO 2015/191677, and WO2015/157257.

The Pim inhibitors of the present invention can further be used incombination with other methods of treating cancers, for example bychemotherapy, irradiation or surgery. The compounds can be administeredin combination with one or more anti-cancer drugs, such as achemotherapeutics. Example chemotherapeutics include any of: abarelix,aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine,anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab,bexarotene, bleomycin, bortezombi, bortezomib, busulfan intravenous,busulfan oral, calusterone, capecitabine, carboplatin, carmustine,cetuximab, chlorambucil, cisplatin, cladribine, clofarabine,cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparinsodium, dasatinib, daunorubicin, decitabine, denileukin, denileukindiftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolonepropionate, eculizumab, epirubicin, erlotinib, estramustine, etoposidephosphate, etoposide, exemestane, fentanyl citrate, filgrastim,floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib,gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelinacetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinibmesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate,lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole,lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine,methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone,nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin,paclitaxel, pamidronate, panitumumab, pegaspargase, pegfilgrastim,pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine,quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib,streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide,teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan,toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard,valrubicin, vinblastine, vincristine, vinorelbine, vorinostat andzoledronate.

In some embodiments Pim inhibitors of the invention can be combined withcytarabine.

Other anti-cancer agent(s) include antibody therapeutics such astrastuzumab (Herceptin), antibodies to costimulatory molecules such asCTLA-4, 4-1BB, PD-1 and PD-L1, or antibodies to cytokines (IL-10, TGF-β,etc.).

The Pim inhibitors of the present invention can further be used incombination with one or more anti-inflammatory agents, steroids,immunosuppressants or therapeutic antibodies.

The Pim inhibitors of the present invention can be used in combinationwith one or more immune check point inhibitors. Exemplary immunecheckpoint inhibitors include inhibitors against immune checkpointmolecules such as CD27, CD28, CD40, CD122, CD96, CD73, CD47, OX40, GITR,CSF1R, JAK (e.g., JAK1 and/or JAK2), PI3K delta, PI3K gamma, TAM,arginase, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA,CTLA-4, LAG3, TIM3, VISTA, PD-1, PD-L1 and PD-L2. In some embodiments,the immune checkpoint molecule is a stimulatory checkpoint moleculeselected from CD27, CD28, CD40, ICOS, OX40, GITR and CD137. In someembodiments, the immune checkpoint molecule is an inhibitory checkpointmolecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3,PD-1, TIM3, and VISTA. In some embodiments, the compounds providedherein can be used in combination with one or more agents selected fromKIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors,2B4 inhibitors and TGFR beta inhibitors.

In some embodiments, immune checkpoint inhibitors include inhibitorsagainst immune checkpoint molecules such as JAK1 and/or JAK2.

In some embodiments, immune checkpoint inhibitors include inhibitorsagainst immune checkpoint molecules such as CD96.

In some embodiments, the inhibitor of an immune checkpoint molecule isanti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In someembodiments, the anti-PD-1 monoclonal antibody is nivolumab,pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, orAMP-224. In some embodiments, the anti-PD-1 monoclonal antibody isnivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibodyis pembrolizumab.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In someembodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736,MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments,the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In someembodiments, the anti-CTLA-4 antibody is ipilimumab.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments,the anti-LAG3 antibody is BMS-986016 or LAG525.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments,the anti-GITR antibody is TRX518 or MK-4166. In some embodiments, theanti-GITR antibody is INCAGN01876.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of OX40, e.g., an anti-OX40 antibody or OX40L fusionprotein. In some embodiments, the anti-OX40 antibody is MEDI0562. Insome embodiments, the OX40L fusion protein is MEDI6383. In someembodiments, the anti-OX40 antibody is INCAGN01949.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TIM3, e.g., an anti-TIM3 antibody.

In some embodiments Pim inhibitors of the invention can be combined withTIGIT inhibitors.

The Pim inhibitors of the present invention can be used in combinationwith one or more other anti-cancer agents including BET inhibitors(e.g., INCB054329, OTX015, and CPI-0610), LSD1 inhibitors (e.g.,GSK2979552 and INCB059872), HDAC inhibitors (e.g., panobinostat,vorinostat, and entinostat), DNA methyl transferase inhibitors (e.g.,azacitidine and decitabine), and other epigenetic modulators.

In some embodiments Pim inhibitors of the invention can be combined withBET inhibitors. In some embodiments Pim inhibitors of the invention canbe combined with LSD1 inhibitors. In some embodiments Pim inhibitors ofthe invention can be combined with HDAC inhibitors. In some embodimentsPim inhibitors of the invention can be combined with DNA methyltransferase inhibitors.

The Pim inhibitors of the present invention can be used in combinationwith one or more agents for the treatment of diseases such as cancer. Insome embodiments, the agent is an alkylating agent, a proteasomeinhibitor, a corticosteroid, or an immunomodulatory agent. Examples ofan alkylating agent include cyclophosphamide (CY), melphalan (MEL), andbendamustine. In some embodiments, the proteasome inhibitor iscarfilzomib. In some embodiments, the corticosteroid is dexamethasone(DEX). In some embodiments, the immunomodulatory agent is lenalidomide(LEN) or pomalidomide (POM).

When more than one pharmaceutical agent is administered to a patient,they can be administered simultaneously, sequentially, or in combination(e.g., for more than two agents).

IV. Formulation, Dosage Forms and Administration

When employed as pharmaceuticals, the compounds of the invention can beadministered in the form of pharmaceutical compositions. Thus thepresent disclosure provides a composition comprising a compound Formula(I), or a pharmaceutically acceptable salt thereof, or any of theembodiments thereof, and at least one pharmaceutically acceptablecarrier. These compositions can be prepared in a manner well known inthe pharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is indicated and uponthe area to be treated. Administration may be topical (includingtransdermal, epidermal, ophthalmic and to mucous membranes includingintranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalationor insufflation of powders or aerosols, including by nebulizer;intratracheal or intranasal), oral or parenteral. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal intramuscular or injection or infusion; or intracranial,e.g., intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or may be,e.g., by a continuous perfusion pump. Pharmaceutical compositions andFormulations for topical administration may include transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, the compound of the invention or apharmaceutically acceptable salt thereof, in combination with one ormore pharmaceutically acceptable carriers (excipients). In someembodiments, the composition is suitable for topical administration. Inmaking the compositions of the invention, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, e.g., a capsule, sachet, paper, orother container. When the excipient serves as a diluent, it can be asolid, semi-solid, or liquid material, which acts as a vehicle, carrieror medium for the active ingredient. Thus, the compositions can be inthe form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, e.g., up to 10% by weightof the active compound, soft and hard gelatin capsules, suppositories,sterile injectable solutions and sterile packaged powders.

In preparing a Formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe Formulation, e.g., about 40 mesh.

The compounds of the invention may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other Formulation types. Finely divided(nanoparticulate) preparations of the compounds of the invention can beprepared by processes known in the art see, e.g., WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup and methyl cellulose. TheFormulations can additionally include: lubricating agents such as talc,magnesium stearate and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

In some embodiments, the pharmaceutical composition comprises silicifiedmicrocrystalline cellulose (SMCC) and at least one compound describedherein, or a pharmaceutically acceptable salt thereof. In someembodiments, the silicified microcrystalline cellulose comprises about98% microcrystalline cellulose and about 2% silicon dioxide w/w.

In some embodiments, the composition is a sustained release compositioncomprising at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier. In some embodiments, the composition comprises at least onecompound described herein, or a pharmaceutically acceptable saltthereof, and at least one component selected from microcrystallinecellulose, lactose monohydrate, hydroxypropyl methylcellulose andpolyethylene oxide. In some embodiments, the composition comprises atleast one compound described herein, or a pharmaceutically acceptablesalt thereof, and microcrystalline cellulose, lactose monohydrate andhydroxypropyl methylcellulose. In some embodiments, the compositioncomprises at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and microcrystalline cellulose, lactosemonohydrate and polyethylene oxide. In some embodiments, the compositionfurther comprises magnesium stearate or silicon dioxide. In someembodiments, the microcrystalline cellulose is Avicel PH102™. In someembodiments, the lactose monohydrate is Fast-flo 316™. In someembodiments, the hydroxypropyl methylcellulose is hydroxypropylmethylcellulose 2208 K4M (e.g., Methocel K4 M Premier™) and/orhydroxypropyl methylcellulose 2208 K100LV (e.g., Methocel KOOLV™). Insome embodiments, the polyethylene oxide is polyethylene oxide WSR 1105(e.g., Polyox WSR 1105™).

In some embodiments, a wet granulation process is used to produce thecomposition. In some embodiments, a dry granulation process is used toproduce the composition.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1,000 mg (1 g), more usually about 100mg to about 500 mg, of the active ingredient. In some embodiments, eachdosage contains about 10 mg of the active ingredient. In someembodiments, each dosage contains about 50 mg of the active ingredient.In some embodiments, each dosage contains about 25 mg of the activeingredient. The term “unit dosage forms” refers to physically discreteunits suitable as unitary dosages for human subjects and other mammals,each unit containing a predetermined quantity of active materialcalculated to produce the desired therapeutic effect, in associationwith a suitable pharmaceutical excipient.

The components used to Formulate the pharmaceutical compositions are ofhigh purity and are substantially free of potentially harmfulcontaminants (e.g., at least National Food grade, generally at leastanalytical grade, and more typically at least pharmaceutical grade).Particularly for human consumption, the composition is preferablymanufactured or Formulated under Good Manufacturing Practice standardsas defined in the applicable regulations of the U.S. Food and DrugAdministration. For example, suitable Formulations may be sterile and/orsubstantially isotonic and/or in full compliance with all GoodManufacturing Practice regulations of the U.S. Food and DrugAdministration.

The active compound may be effective over a wide dosage range and isgenerally administered in a therapeutically effective amount. It will beunderstood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms and the like.

The therapeutic dosage of a compound of the present invention can varyaccording to, e.g., the particular use for which the treatment is made,the manner of administration of the compound, the health and conditionof the patient, and the judgment of the prescribing physician. Theproportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, Formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreFormulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreFormulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preFormulation isthen subdivided into unit dosage forms of the type described abovecontaining from, e.g., about 0.1 to about 1000 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions can be nebulized by use of inert gases. Nebulized solutionsmay be breathed directly from the nebulizing device or the nebulizingdevice can be attached to a face mask, tent, or intermittent positivepressure breathing machine. Solution, suspension, or powder compositionscan be administered orally or nasally from devices which deliver theFormulation in an appropriate manner.

Topical Formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, e.g., liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.,glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be Formulated using isopropyl alcohol and water,suitably in combination with other components such as, e.g., glycerol,hydroxyethyl cellulose, and the like. In some embodiments, topicalFormulations contain at least about 0.1, at least about 0.25, at leastabout 0.5, at least about 1, at least about 2 or at least about 5 wt %of the compound of the invention. The topical Formulations can besuitably packaged in tubes of, e.g., 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers or stabilizers will resultin the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present invention can varyaccording to, e.g., the particular use for which the treatment is made,the manner of administration of the compound, the health and conditionof the patient, and the judgment of the prescribing physician. Theproportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, Formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

V. Labeled Compounds and Assay Methods

The compounds of the invention can further be useful in investigationsof biological processes, including kinase signaling, in normal andabnormal tissues. Thus, another aspect of the present invention relatesto labeled compounds of the invention (radio-labeled,fluorescent-labeled, etc.) that would be useful not only in imagingtechniques but also in assays, both in vitro and in vivo, for localizingand quantitating Pim kinases in tissue samples, including human, and foridentifying Pim kinase ligands by inhibition binding of a labeledcompound. Accordingly, the present invention includes Pim kinase assaysthat contain such labeled compounds.

The present invention further includes isotopically-labeled compounds ofthe invention. An “isotopically” or “radio-labeled” compound is acompound of the invention where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable radionuclides that may be incorporated incompounds of the present invention include but are not limited to ³H(also written as T for tritium), ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O,¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. Theradionuclide that is incorporated in the instant radio-labeled compoundswill depend on the specific application of that radio-labeled compound.For example, for in vitro Pim kinase labeling and competition assays,compounds that incorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹I, ³⁵S or willgenerally be most useful. For radio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I,¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Br or ⁷⁷Br will generally be most useful.

It is to be understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br. In some embodiments, the compoundincorporates 1, 2 or 3 deuterium atoms. Synthetic methods forincorporating radio-isotopes into organic compounds are known in theart.

Specifically, a labeled compound of the invention can be used in ascreening assay to identify and/or evaluate compounds. For example, anewly synthesized or identified compound (i.e., test compound) which islabeled can be evaluated for its ability to bind a Pim-kinase bymonitoring its concentration variation when contacting with the Pimkinase, through tracking of the labeling. For example, a test compound(labeled) can be evaluated for its ability to reduce binding of anothercompound which is known to bind to a Pim kinase (i.e., standardcompound). Accordingly, the ability of a test compound to compete withthe standard compound for binding to the Pim kinase directly correlatesto its binding affinity. Conversely, in some other screening assays, thestandard compound is labeled and test compounds are unlabeled.Accordingly, the concentration of the labeled standard compound ismonitored in order to evaluate the competition between the standardcompound and the test compound, and the relative binding affinity of thetest compound is thus ascertained.

VI. Kits

The present disclosure also includes pharmaceutical kits useful, e.g.,in the treatment or prevention of Pim kinase-associated diseases ordisorders, such as cancer, which include one or more containerscontaining a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of Formula (I), or any of the embodimentsthereof. Such kits can further include one or more of variousconventional pharmaceutical kit components, such as, e.g., containerswith one or more pharmaceutically acceptable carriers, additionalcontainers, etc., as will be readily apparent to those skilled in theart. Instructions, either as inserts or as labels, indicating quantitiesof the components to be administered, guidelines for administration,and/or guidelines for mixing the components, can also be included in thekit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples have been found to bePim-kinase inhibitors according to at least one assay described herein.

EXAMPLES

Experimental procedures for compounds of the invention are providedbelow. Preparatory LC-MS purifications of some of the compounds preparedwere performed on Waters mass directed fractionation systems. The basicequipment setup, protocols, and control software for the operation ofthese systems have been described in detail in the literature. See e.g.“Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K.Blom, J. Combi. Chem., 4, 295 (2002); “Optimizing Preparative LC-MSConfigurations and Methods for Parallel Synthesis Purification”, K.Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi.Chem., 5, 670 (2003); and “Preparative LC-MS Purification: ImprovedCompound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A.Combs, J. Combi. Chem., 6, 874-883 (2004). The compounds separated weretypically subjected to analytical liquid chromatography massspectrometry (LCMS) for purity check under the following conditions:Instrument; Agilent 1100 series, LC/MSD, Column: Waters Sunfire™ C₁₈ 5μm, 2.1×5.0 mm, Buffers: mobile phase A: 0.025% TFA in water and mobilephase B: 0.025% TFA in acetonitrile; gradient 2% to 80% of B in 3 min.with flow rate 1.5 mL/min.

Some of the compounds prepared were also separated on a preparativescale by reverse-phase high performance liquid chromatography (RP-HPLC)with MS detector or flash chromatography (silica gel) as indicated inthe Examples. Typical preparative reverse-phase high performance liquidchromatography (RP-HPLC) column conditions are as follows:

pH=2 purifications: Waters Sunfire™ C₁₈ 5 μm, 19×100 mm column, elutingwith mobile phase A: 0.1% TFA (trifluoroacetic acid) in water and mobilephase B: 0.1% TFA in acetonitrile; the flow rate was 30 mL/min., theseparating gradient was optimized for each compound using the CompoundSpecific Method Optimization protocol as described in the literature[see “Preparative LCMS Purification: Improved Compound Specific MethodOptimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem.,6, 874-883 (2004)]. Typically, the flow rate used with the 30×100 mmcolumn was 60 mL/min.

pH=10 purifications: Waters XBridge™ C₁₈ 5 μm, 19×100 mm column, elutingwith mobile phase A: 0.15% NH₄OH in water and mobile phase B: 0.15%NH₄OH in acetonitrile; the flow rate was 30 mL/min., the separatinggradient was optimized for each compound using the Compound SpecificMethod Optimization protocol as described in the literature [See“Preparative LCMS Purification: Improved Compound Specific MethodOptimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem.,6, 874-883 (2004)]. Typically, the flow rate used with 30×100 mm columnwas 60 mL/min.

Intermediate 1 tert-Butyl((3R,4R,5S)-1-(3-{[(6-bromo-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate

Step 1. (6-Bromo-5-fluoropyridin-2-yl)methanol

Methyl 6-bromo-5-fluoropyridine-2-carboxylate (Frontier Scientific, 2.50g, 10.7 mmol) was dissolved in methanol (20.0 mL) and the reactionmixture was cooled to 0° C. Then sodium tetrahydroborate (1.2 g, 32mmol) was slowly added to the reaction mixture and the reaction mixturewas allowed to warm to room temperature and stirring continued for 1 hat room temperature. After this time, water was added to the reactionmixture and product was extracted with EtOAc. Combined organic fractionswere washed with brine, dried over Na₂SO₄ and solvents were evaporatedunder reduced pressure. The resulting product was used in the next stepwithout further purification (2.2 g, 98%). LCMS calc. for C₆H₆BrFNO(M+H)⁺ m/z=206.0. found 205.9.

Step 2. 6-Bromo-5-fluoropyridine-2-carbaldehyde

To a stirred solution of (6-bromo-5-fluoropyridin-2-yl)methanol (2.15 g,10.4 mmol) in DCM (70 mL) at 0° C. were added pyridine (1.0 mL, 12 mmol)and Dess-Martin periodinane (4.65 g, 11.0 mmol). The reaction mixturewas stirred at room temperature for 3 h. Then saturated solutions ofNaHCO₃ in water (40 mL) and Na₂S₂O₃ in water (20 mL) were added and thereaction mixture was stirred for 30 min. Then product was extracted withDCM. Combined organic fractions were washed with brine, dried overNa₂SO₄ and solvents were evaporated under reduced pressure. The crudeproduct was purified by Biotage Isolera to give the desired compound(1.8 g, 85%). LCMS calc. for C₆H₄BrFNO (M+H)⁺ m/z=204.0. found: 204.0.

Step 3. tert-butyl(4R)-4-{(1R,2R)-3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-1-hydroxy-2-methyl-3-oxopropyl}-2,2-dimethyl-1,3-oxazolidine-3-carboxylate

To a solution of (R)-3-(1-oxopropyl)-4-benzyl-2-oxazolidinone (12 g, 51mmol) in DCM (300 mL) (0.13 M), 1.0 M TiCl₄ in DCM (51 mL, 51 mmol) wasadded at −40° C. The mixture was stirred at −40° C. for 10 min., thenDIPEA (22 mL, 130 mmol) was added, forming a dark red solution. Themixture was stirred at 0° C. for 20 min. tert-Butyl(4R)-4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (12 g, 51 mmol)in DCM (100 mL) (0.5 M) was then added dropwise and the resultingmixture was stirred for 1.5 h at 0° C. LCMS showed 2 peaks with a masscorresponding to the sub-title compound, one major peak and one min. orpeak (5:2). The reaction mixture was quenched by the addition of aq.NH₄Cl solution and the mixture was extracted with DCM. The organic phasewas separated, washed with brine, dried over MgSO₄, concentrated underreduced pressure, and purified by chromatography on silica gel (0-40%EtOAc/hexane) to give 8 g (30% yield) of the sub-title compound as acolorless oil. LCMS calc. for C₂₄H₃₅N₂O₇ (M+H)⁺: m/z=463.2. found:463.1.

Step 4. tert-butyl(4R)-4-((1R,2R)-3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-1-{[tert-butyl(dimethyl)silyl]oxy}-2-methyl-3-oxopropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate

To a solution of tert-butyl(4R)-4-{(1R,2R)-3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-1-hydroxy-2-methyl-3-oxopropyl}-2,2-dimethyl-1,3-oxazolidine-3-carboxylate(12.1 g, 26.2 mmol) and 2,6-lutidine (5.4 mL, 47 mmol) in DCM (260 mL)(0.1 M) was added tert-butyldimethylsilyl trifluoromethanesulfonate(8.41 mL, 36.6 mmol) at −40° C. The mixture was stirred at −40° C. for 2h. The reaction mixture was diluted with DCM, washed with saturated aq.NaHCO₃ solution, dried over Na₂SO₄, concentrated under reduced pressure,and purified by chromatography on silica gel (0-20% EtOAc/hexane) togive 14 g (92.8% yield) of the sub-title compound as a colorless gel.LCMS calc. for C₂₅H₄₁N₂O₅Si (M+H-Boc+H)⁺: m/z=477.3. found: 477.1.

Step 5. tert-butyl(4R)-4-((1R,2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-3-hydroxy-2-methylpropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate

To a solution of tert-butyl(4R)-4-((1R,2R)-3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-1-{[tert-butyl(dimethyl)silyl]oxy}-2-methyl-3-oxopropyl)-2,2-dimethyl-1,3-oxaxazolidine-3-carboxylate(14.0 g, 24.3 mmol) and EtOH (4.2 mL, 73 mmol) in THF (300 mL) (0.09 M)was added LiBH₄ (1.6 g, 73 mmol) at −30° C. The mixture allowed to warmto 0° C. and stirred overnight. The reaction mixture was diluted withEt₂O and 1 M NaOH was added. The resulting mixture was extracted withEtOAc and the organic extract was washed with brine, dried over Na₂SO₄,concentrated under reduced pressure, and purified by chromatography onsilica gel (0-20% EtOAc/hexane) to give 4.1 g (42% yield) of thesub-title compound as a colorless oil. LCMS calc. forC₁₅H₃₄NO₃Si(M+H-Boc+H)⁺: m/z=304.2. found: 304.1.

Step 6. tert-butyl(4R)-4-((1R,2S)-3-azido-1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate

To a mixture of tert-butyl(4R)-4-((1R,2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-3-hydroxy-2-methylpropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate(8.20 g, 20.3 mmol), diisopropyl azodicarboxylate (8.0 mL, 41 mmol) andPPh₃ (11 g, 41 mmol) in THF (100 mL) (0.18 M), diphenylphosphonic azide(8.8 mL, 41 mmol) was added. The mixture was stirred at room temperatureovernight. The mixture was concentrated under reduced pressure, and theresidue was purified by chromatography on silica gel (0-15%EtOAc/hexane) to give 5.2 g (60% yield) of the sub-title compound as ayellowish oil. LCMS calc. for C₂₀H₄₁N₄O₄Si (M+H)⁺: m/z=429.3. found:429.1.

Step 7. tert-butyl[(1R,2R,3S)-4-azido-2-{[tert-butyl(dimethyl)silyl]oxy}-1-(hydroxymethyl)-3-methylbutyl]carbamate

A solution of tert-butyl(4R)-4-((1R,2S)-3-azido-1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate(10.5 g, 24.5 mmol) in EtOH (70 mL) was added pyridiniump-toluenesulfonate (12.3 g, 49.0 mmol) and the mixture was heated underreflux for 2 days.

The volatiles were removed under reduced pressure and the residue wasdissolved in DCM (200 mL) (0.1 M). To the resulting solution were addedDIPEA (8.53 mL, 49.0 mmol) and di-tert-butyldicarbonate (6.42 g, 29.4mmol). The reaction mixture was stirred at room temperature for 5 h. Themixture was concentrated under reduced pressure and purified bychromatography on silica gel (0-25% EtOAc/Hexane) to give 5.8 g (61%yield) of the sub-title compound as a colorless oil. LCMS calc. forC₁₂H₂₉N₄O₂Si (M+H-Boc+H)⁺: m/z=289.2. found: 289.1.

Step 8.(2R,3R,4S)-5-azido-2-[(tert-butoxycarbonyl)amino]-3-{[tert-butyl(dimethyl)silyl]oxy}-4-methylpentylmethanesulfonate

To a solution of tert-butyl[(1R,2R,3S)-4-azido-2-{[tert-butyl(dimethyl)silyl]oxy}-1-(hydroxymethyl)-3-methylbutyl]carbamate(5.80 g, 14.9 mmol) in pyridine (75 mL) at 0° C. was addedmethanesulfonyl chloride (1.50 mL, 19.4 mmol) and DMAP (0.36 g, 3.0mmol). The mixture was stirred at 0° C. for 1 h. The solution wasdiluted with EtOAc, washed with saturated aq. NaHCO₃ solution,concentrated under reduced pressure, and purified by chromatography onsilica gel (0-25% EtOAc/Hexane) to give 4.8 g (69% yield) of thesub-title compound as a colorless oil. LCMS calc. for C₁₃H₃₁N₄O₄SSi(M+H-Boc)⁺: m/z=367.2. found: 367.2.

Step 9. tert-butyl((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate

A solution of(2R,3R,4S)-5-azido-2-[(tert-butoxycarbonyl)amino]-3-{[tert-butyl(dimethyl)silyl]oxy}-4-methylpentylmethanesulfonate (4.25 g, 9.11 mmol) in MeOH (100 mL) (0.09M) wasdeoxygenated with a stream of N₂ for 20 min. DIPEA (4.0 mL, 23 mmol) wasadded, followed by mixture of 10% Pd on carbon (0.97 g, 0.91 mmol). Thereaction mixture was stirred under a balloon containing H₂ for 2 h. Thesolution was filtered through a pad of diatomaceous earth and rinsedwith MeOH. The filtrate was concentrated under reduced pressure to give2.10 g (66% yield) of the sub-title compound as a white solid. LCMScalc. for C₁₇H₃₇N₂O₃Si(M+H)⁺: m/z=345.3. found: 345.1.

Step 10. tert-butyl[(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methyl-1-(3-nitropyridin-4-yl)piperidin-3-yl]carbamate

A mixture of 4-chloro-3-nitropyridine (from Aldrich, 150.0 mg, 0.9461mmol) and tert-butyl((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(300.0 mg, 0.8707 mmol) and TEA (0.3763 mL, 2.700 mmol) in IPA (10.0 mL)was stirred at 60° C. for 2 h. The reaction mixture was concentratedunder reduced pressure and the residue was purified by columnchromatography on silica gel using CombiFlash® apparatus (eluting with 0to 30% EtOAc in hexane) to give 100 mg (24% yield) of the sub-titlecompound. LCMS calc. for C₂₂H₃₉N₄O₅Si (M+H)⁺: m/z=467.3. found: 467.1.

Step 11. tert-butyl((3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate

A mixture of tert-butyl [(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methyl-1-(3-nitropyridin-4-yl)piperidin-3-yl]carbamate(100.00 mg, 0.27858 mmol), AcOH (10.00 mL) and iron powder (558.4 mg,9.999 mmol) was stirred at ambient temperature for 2 h. The mixture wasdiluted with 30 mL of EtOAc and filtered through a pad of diatomaceousearth. The combined organic filtrate was concentrated under reducedpressure. The residue was diluted with EtOAc and washed with aq. Na₂CO₃solution and 0.2 M NaOH. The organic phase was concentrated underreduced pressure to give 50 mg (47% yield) of the title compound. LCMScalc. for C₂₂H₄₁N₄O₃Si (M+H)⁺: m/z=437.3. found: 437.1.

Step 12. tert-Butyl((3R,4R,5S)-1-(3-{[(6-bromo-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate

tert-Butyl((3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(350 mg, 0.80 mmol) and 6-bromo-5-fluoropyridine-2-carbaldehyde(Prepared in Step 2, 188 mg, 0.922 mmol) were dissolved in toluene (6.0mL). Then catalytic amount of acetic acid was added and the reactionmixture was heated at 100° C. for 2 h. After imine formation wascomplete as determined by LCMS, the reaction was cooled to roomtemperature and toluene was evaporated under reduced pressure. Theresulting intermediate imine was dissolved in methanol (5.0 mL) and theresulting reaction mixture was cooled to 0° C. Then sodiumtetrahydroborate (61 mg, 1.6 mmol) was slowly added and the reactionmixture was stirred at room temperature for 30 min. After this time,water was added to the reaction mixture and product was extracted withEtOAc. Combined organic fractions were washed with brine, dried overNa₂SO₄ and solvents were evaporated under reduced pressure. The crudeproduct was purified by Biotage Isolera to give the desired compound(400 mg, 80%). LCMS calc. for C₂₈H₄₄BrFN₅O₃Si (M+H)⁺ m/z=624.2. found:624.2.

Intermediate 2 tert-Butyl[(3S,5R)-1-(3-{[(6-bromo-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate

Step 1. 1-tert-butyl 2-methyl(2S,4R)-4-methyl-5-oxopyrrolidine-1,2-dicarboxylate

A solution of 1-tert-butyl 2-methyl(2S)-5-oxopyrrolidine-1,2-dicarboxylate (16.1 g, 66.2 mmol) in THF (100mL) was cooled to −78° C. LiHMDS in THF (1.0 M, 68.2 mL, 68.2 mmol) wasadded dropwise over 5 min. The resulting mixture was stirred at −78° C.for 35 min., then MeI (10.0 mL, 160 mmol) was added. The reactionmixture was allowed to warm to room temperature slowly overnight. Thereaction was quenched with AcOH (7.5 mL, 130 mmol) and water (5 mL) andthen concentrated under reduced pressure. The concentrated residue wasfurther diluted with water and extracted with EtOAc (3 times). Thecombined extracts were washed with water and brine, dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by silica gel column and eluted with 0-50% EtOAc/Hexanes over45 min. Fractions were checked by TLC (MoSO₄ stain) and LCMS. 6.1 g (35%yield) of the sub-title compound was obtained. LCMS calc. for C₇H₁₂NO₃(M+H-Boc+H)⁺: m/z=158.1. found: 158.1.

Step 2. tert-butyl[(1S,3R)-4-hydroxy-1-(hydroxymethyl)-3-methylbutyl]carbamate

A solution of 1-tert-butyl 2-methyl(2S,4R)-4-methyl-5-oxopyrrolidine-1,2-dicarboxylate (11.0 g, 42.8 mmol)in THF (100 mL) was cooled to 0° C. then LiBH₄ (2.8 g, 130 mmol) andthen EtOH (22 mL) were added. The mixture was slowly warmed to roomtemperature and stirred for 4 h. The reaction was quenched with waterthen extracted with EtOAc (3 times). The combined extracts were driedover Na₂SO₄, filtered, and concentrated under reduced pressure to give4.5 g (45% yield) of the crude sub-title compound. The crude product wasused without further purification.

Step 3. tert-butyl [(3S,5R)-1-benzyl-5-methylpiperidin-3-yl]carbamate

A solution of tert-butyl[(1S,3R)-4-hydroxy-1-(hydroxymethyl)-3-methylbutyl]carbamate (9.50 g,40.7 mmol) in DCM (200 mL) was cooled to 0° C. TEA (23 mL, 160 mmol) wasadded followed by dropwise addition of methanesulfonyl chloride (9.4 mL,120 mmol). The clear solution became cloudy and yellow and the mixturewas stirred at 0° C. for 1 h. The mixture was diluted with DCM andwashed with saturated aq. NaHCO₃ and water. The organic layer was driedover Na₂SO₄, filtered, and concentrated under reduced pressure to givean intermediate mesylate as a yellow oil that was used immediately forthe next step.

The intermediate mesylate and benzylamine (90 mL, 800 mmol) werecombined in microwave vial, sealed and heated at 70° C. overnight. After18 h, the mixture was quenched with 10% aq. NaOH. The mixture was thenextracted with hexanes (3 times). The combined extracts were washed withbrine, dried over MgSO₄, filtered, and concentrated under reducedpressure. The residue was purified on a silica gel column and elutedwith 0-40% EtOAc/hexane over 34 min. to give 6.0 g (49% yield) of thesub-title compound as a white solid. LCMS calc. for C₁₈H₂₉N₂O₂ (M+H)⁺:m/z=305.2. found: 305.1.

Step 4. tert-butyl [(3S,5R)-5-methylpiperidin-3-yl]carbamate

A mixture of tert-butyl[(3S,5R)-1-benzyl-5-methylpiperidin-3-yl]carbamate (4.5 g, 15 mmol),AcOH (2.0 mL, 35 mmol) and 10% Pd on carbon (1.6 g, 1.5 mmol) in EtOH(100 mL) was stirred in a Par-shaker under H₂ (50 psi) overnight. Themixture was filtered through a pad of diatomaceous earth andconcentrated under reduced pressure. The residue was diluted with DCM(500 mL) and washed with saturated aq. NaHCO₃ solution. The aqueouslayer was extracted twice with DCM. The combined DCM extract was driedover Na₂SO₄, and concentrated under reduced pressure to give 2.2 g (67%yield) of the sub-title compound as a white solid. LCMS calc. forC₁₁H₂₃N₂O₂ (M+H)⁺: m/z=: 215.2. found: 215.1.

Step 5. tert-butyl[(3S,5R)-5-methyl-1-(3-nitropyridin-4-yl)piperidin-3-yl]carbamate

A mixture of 4-chloro-3-nitropyridine (740 mg, 4.7 mmol), tert-butyl[(3S,5R)-5-methylpiperidin-3-yl]carbamate (1000.0 mg, 4.67 mmol) andDIPEA (2.4 mL, 14 mmol) was irradiated in a microwave oven for 1 h at130° C. The reaction mixture was concentrated under reduced pressure andthe residue was purified by column chromatography on silica gel using aCombiFlash® apparatus eluting with EtOAc/hexane (10-60%). Thepurification gave 1.21 g (80% yield) of the sub-title compound as acolorless oil. LCMS calc. for C₁₆H₂₅N₄O₄ (M+H)⁺: m/z=337.2. found:337.1.

Step 6. tert-butyl[(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate

A mixture of tert-butyl[(3S,5R)-5-methyl-1-(3-nitropyridin-4-yl)piperidin-3-yl]carbamate (100mg, 0.3 mmol), iron powder (0.072 g, 1.3 mmol), AcOH (2.0 mL, 35 mmol)and water (0.2 mL, 10 mmol) was stirred at room temperature for 60 min.When the reaction was complete, the reaction mixture was concentratedunder reduced pressure, diluted with EtOAc, filtered through a pad ofdiatomaceous earth, washed with aqueous NaHCO₃ solution, washed withwater and brine, dried over Na₂SO₄, and concentrated under reducedpressure to give 60 mg (60% yield) of the title compound as a brownsolid. LCMS calc. for C₁₆H₂₇N₄O₂ (M+H)⁺: m/z=307.1. found: 307.1.

Step 7. tert-Butyl[(3S,5R)-1-(3-{[(6-bromo-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate

tert-Butyl[(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate (388mg, 1.27 mmol) and 6-bromo-5-fluoropyridine-2-carbaldehyde (Prepared inIntermediate 1, Step 2; 340 mg, 1.6 mmol) were dissolved in toluene(11.0 mL). Then catalytic amount of acetic acid was added and thereaction mixture was heated at 100° C. for 2 h. After imine formationwas complete as determined by LCMS, the reaction mixture was cooled toroom temperature and toluene was evaporated under reduced pressure. Theresulting intermediate imine was dissolved in methanol (7.0 mL) andresulting reaction mixture was cooled to 0° C. Then sodiumtetrahydroborate (120 mg, 3.2 mmol) was slowly added and the reactionmixture was stirred at room temperature for 30 min. After this time,water was added to the reaction mixture and product was extracted withEtOAc. Combined organic fractions were washed with brine, dried overNa₂SO₄ and solvents were evaporated under reduced pressure. The crudeproduct was purified by Biotage Isolera to give the desired compound(526 mg, 84%). LCMS calc. for C₂₂H₃₀BrFN₅O₂ (M+H)⁺ m/z=494.2. found:494.1.

Intermediate 3 tert-Butyl((3S,5R)-1-(3-(((6-bromo-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl)carbamate

Step 1. Benzyl(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)piperidine-1-carboxylate

To a round bottom flask containingcis-3-(Boc-amino)-5-(trifluoromethyl)piperidine (Molbridge, 10.00 g,37.27 mmol) and NaHCO₃ (18.8 g, 224 mmol), THF (200 mL) was added,followed by water (200 mL). Benzyl chloroformate (20.1, g, 112 mmol) wasthen added dropwise over a period of 30 min. via a syringe pump. Themixture was stirred at room temperature for 2 h. The mixture was thendiluted with EtOAc and water. The layers were separated and the organiclayer was washed with brine, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The resulting residue was purifiedby flash chromatography on silica gel (340 g, 15% EtOAc in hexanes) togive a white foamy solid which was subjected to chiral HPLC separation(Phenomenex Lux Cellulose C-1, 5 μm, 21.2×250 mm column, eluting with15% EtOH in hexanes, at flow rate of 18 mL/min., with a loading of 100mg in 1000 μL at 220 nm wavelength) to give the sub-title compound(retention time: 9.1 min.) as a white foamy solid (6.51 g, 43%). LCMScalc. for C₁₉H₂₅F₃N₂NaO₄ (M+Na)⁺: m/z=425.2. found: 425.2. The sub-titlecompound is assigned as the (3S,5R) isomer. The alternative (3R,5S)isomer can be obtained from the same separation.

Step 2. tert-Butyl [(3S,5R)-5-(trifluoromethyl)piperidin-3-yl]carbamate

A mixture of benzyl(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)piperidine-1-carboxylate(3.86 g, 9.59 mmol) in MeOH (50 mL) was hydrogenated in the presence of10% Pd on carbon (0.30 g) under 25 psi of hydrogen for 2 h. The reactionmixture was filtered and the filtrate was concentrated under reducedpressure to give the sub-title compound (2.6 g, 100%). LCMS calc. forC₁₁H₂₀F₃N₂O₂(M+H)⁺: m/z=269.1. found: 269.2.

Step 3: tert-Butyl[(3S,5R)-1-(3-nitropyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate

A mixture of 4-chloro-3-nitropyridine (580 mg, 3.6 mmol), tert-butyl[(3S,5R)-5-(trifluoromethyl)piperidin-3-yl]carbamate (800 mg, 3 mmol),isopropyl alcohol (5.0 mL) and DIPEA (1.0 mL, 6.0 mmol) was stirred at80° C. overnight. The reaction mixture was concentrated under reducedpressure and the residue was purified by column chromatography on silicagel using CombiFlash® apparatus eluting with 50-100% EtOAc/hexanes. Thepurification gave 1.0 g (80% yield) of the sub-title compound as ayellow solid. LCMS calc. for C₁₆H₂₂F₃N₄O₄ (M+H)⁺: m/z=: 391.2. found:391.1.

Step 4: tert-Butyl[(3S,5R)-1-(3-aminopyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate

A mixture of tert-butyl[(3S,5R)-1-(3-nitropyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate(1 g, 2 mmol), iron powder (0.57 g, 10 mmol), AcOH (16 mL) and water (2mL) was stirred at room temperature for 1 h. The mixture was allowed tocool to room temperature, concentrated under reduced pressure and theresulting residue was diluted with EtOAc. The resulting mixture wasfiltered through a diatomaceous earth pad. The filtrate was concentratedunder reduced pressure, and the residue was dissolved in 1 M NaOHaqueous solution and extracted with EtOAc (100 mL×3). The combinedorganic layers were washed with water and brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure to give 0.9 g (100%yield) of the sub-title compound as a brown solid. LCMS calc. forC₁₆H₂₄F₃N₄O₂(M+H)⁺: m/z=: 361.2. found: 361.1.

Step 5. tert-butyl((3S,5R)-1-(3-(((6-bromo-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl)carbamate

tert-Butyl(3S,5R)-1-(3-aminopyridin-4-yl)-5-(trifluoromethyl)piperidin-3-ylcarbamate(457 mg, 1.27 mmol) and 6-bromo-5-fluoropyridine-2-carbaldehyde(Prepared in Intermediate 1, Step 2; 340 mg, 1.6 mmol) were dissolved intoluene (11.0 mL). Then catalytic amount of acetic acid was added andthe reaction mixture was heated at 100° C. for 2 h. After imineformation was complete as determined by LCMS, the reaction mixture wascooled to room temperature and toluene was evaporated under reducedpressure. The resulting intermediate imine was dissolved in methanol(7.0 mL) and resulting reaction mixture was cooled to 0° C. Then sodiumtetrahydroborate (120 mg, 3.2 mmol) was slowly added and the reactionmixture was stirred at room temperature for 30 min. After this time,water was added to the reaction mixture and product was extracted withEtOAc. Combined organic fractions were washed with brine, dried overNa₂SO₄ and solvents were evaporated under reduced pressure. The crudeproduct was purified by Biotage Isolera to give the desired compound(536 mg, 77%). LCMS calc. for C₂₂H₂₇BrF₄N₅O₂ (M+H)⁺ m/z=548.1. found:548.1.

Intermediate 4 tert-Butyl((3R,4R,5S)-1-(3-{[(3-bromofuro[3,2-b]pyridin-5-yl)methyl]amino}pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate

Step 1. Methyl 5-hydroxypyridine-2-carboxylate

Methanol (70 mL) was added to 5-hydroxypyridine-2-carboxylic acid(Combi-Blocks, 5.01 g, 36.0 mmol). Then sulfuric acid (5.8 mL, 110 mmol)was carefully added to the reaction mixture. Reaction mixture wasstirred at 75° C. overnight. After this time the solvent was evaporatedand the product was dissolved in EtOAc. To the resultant solution wasadded saturated aq. NaHCO₃ to pH 3. Formed precipitate was collected byfiltration and dried under vacuum. The rest of the product was extractedwith EtOAc. Collected organic fractions were washed with brine, driedover Na₂SO₄ and the solvent was evaporated under reduced pressure.Obtained solid product (5.3 g, 96%) was used in the next step withoutfurther purification. LCMS calc. for C₇H₈NO₃ (M+H)⁺ m/z=154.1. found:154.1.

Step 2. Methyl 5-hydroxy-6-iodopyridine-2-carboxylate

Iodine (3.331 g, 13.12 mmol) was added to the mixture of sodiumcarbonate (3.034 g, 28.63 mmol) and methyl5-hydroxypyridine-2-carboxylate (2.0 g, 13 mmol) in water (60 mL). Thereaction mixture was stirred at room temperature overnight. After thistime reaction was acidified to pH 5 by the addition of 1M solution ofHCl and the desired product was extracted with EtOAc. Collected organicfractions were washed with brine, dried over Na₂SO₄ and the solventevaporated under reduced pressure to give the product as white solid(3.4 g, 93%). Obtained product was used in the next step without furtherpurification. LCMS calc. for C₇H₇INO₃ (M+H)⁺ m/z=280.0. found: 279.9.

Step 3. Methyl 2-(trimethylsilyl)furo[3,2-b]pyridine-5-carboxylate

Methyl 5-hydroxy-6-iodopyridine-2-carboxylate, copper(I)iodide (360 mg,1.9 mmol) and dichloro[bis(triphenylphosphonio)]palladate (1.1 g, 1.6mmol) were placed in a vial. The vial was then evacuated and backfilledwith nitrogen three times. After this 1,4-dioxane (120 mL) andtriethylamine (5.69 mL, 40.8 mmol) were added to the reaction mixture.Reaction mixture was stirred at room temperature for 5 min. Then(trimethylsilyl)acetylene (4.62 mL, 32.7 mmol) was added and thereaction mixture was stirred at 60° C. for 3 h. After this time reactionmixture was quenched by the addition of water and the product wasextracted with EtOAc. Collected organic fractions were washed withbrine, dried over Na₂SO₄ and the solvents were evaporated under reducedpressure. The crude product was purified by Biotage Isolera to give thedesired compound as brown oil (4.2 g, 62%). LCMS calc. for C₁₂H₁₆NO₃Si(M+H)⁺ m/z=250.1. found: 250.0.

Step 4. Methyl furo[3,2-b]pyridine-5-carboxylate

Potassium carbonate (7.0 g, 50 mmol) was added to a solution of methyl2-(trimethylsilyl)furo[3,2-b]pyridine-5-carboxylate (4.2 g, 17 mmol) inmethanol (50 mL). Reaction mixture was stirred at room temperature for 2h. Then water was added and the product was extracted with EtOAc.Collected organic fractions were washed with brine, dried over Na₂SO₄and the solvents were evaporated under reduced pressure. Obtainedproduct was used in the next step without further purification (2.1 g,72%). LCMS calc. for C₉H₈NO₃ (M+H)⁺ m/z=178.1. found: 178.1.

Step 5. Methyl 2,3-dibromo-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate

Bromine (3.1 mL, 60. mmol) was slowly added to a solution of methylfuro[3,2-b]pyridine-5-carboxylate (2.138 g, 12.07 mmol) in DCM (50 mL)and the reaction mixture was stirred at room temperature for 3 h. Thenexcess of bromine was carefully quenched by the addition of thesaturated solution of Na₂S₂O₃. The product was extracted with DCM.Collected organic fractions were washed with brine, dried over Na₂SO₄and the solvents were evaporated under reduced pressure. Obtained crudeproduct was purified by Biotage Isolera to give the desired compound(1.65 g, 41%). LCMS calc. for C₉H₈Br₂NO₃ (M+H)⁺ m/z=337.9. found: 337.9.

Step 6. 3-Bromofuro[3,2-b]pyridine-5-carboxylic acid

1.0 M Solution of potassium hydroxide in ethanol (15 mL, 15 mmol) wasadded to a solution of methyl2,3-dibromo-2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate (1.65 g, 4.90mmol) in tetrahydrofuran (15 mL). The reaction mixture was stirred atroom temperature for 20 min. After this time, it was diluted with EtOAcand water was added. The reaction was neutralized by the addition of the1M solution of HCl in water and the desired product was extracted withEtOAc. Collected organic fractions were washed with brine, dried overNa₂SO₄ and solvents were evaporated under reduced pressure to give thedesired compound (0.94 g, 79%), which was used in the next step withoutfurther purification. LCMS calc. for C₈H₅BrNO₃ (M+H)⁺ m/z=242.0. found:241.

Step 7. (3-Bromofuro[3,2-b]pyridin-5-yl)methanol

To a solution of 3-bromofuro[3,2-b]pyridine-5-carboxylic acid (334 mg,1.38 mmol) and triethylamine (202 μL, 1.45 mmol) in tetrahydrofuran (10mL) was slowly added isobutyl chloroformate (0.188 mL, 1.45 mmol).Reaction was stirred at room temperature for 1 h. The formed precipitatewas filtered and to obtained clear solution was slowly added solution ofsodium tetrahydroborate (100 mg, 3.2 mmol) in water (1 mL). Reactionmixture was stirred at room temperature for 30 min. Then water was addedand the product was extracted with EtOAc. Combined organic fractionswere washed with brine and dried with Na₂SO₄. After evaporation of thesolvents under reduced pressure, obtained product was used in the nextstep without further purification (310 mg, 99%). LCMS calc. forC₈H₇BrNO₂ (M+H)⁺ m/z=228.0. found 228.0.

Step 8. 3-Bromofuro[3,2-b]pyridine-5-carbaldehyde

To a stirred solution of (3-bromofuro[3,2-b]pyridin-5-yl)methanol (360mg, 1.6 mmol) in DCM (10 mL) at 0° C. were added pyridine (0.15 mL, 1.9mmol) and Dess-Martin periodinane (0.703 g, 1.66 mmol). The reactionmixture was stirred at room temperature for 3 h. Then saturatedsolutions of NaHCO₃ in water (10 mL) and Na₂S₂O₃ in water (5 mL) wereadded and the reaction mixture was stirred for 30 min. Then product wasextracted with DCM. Combined organic fractions were washed with brine,dried over Na₂SO₄ and solvents were evaporated under reduced pressure.The crude product was purified by Biotage Isolera to give the desiredcompound (280 mg, 78%). LCMS calc. for C₈H₅BrNO₂ (M+H)⁺ m/z=226.0.found: 226.0.

Step 9. tert-Butyl((3R,4R,5S)-1-(3-{[(3-bromofuro[3,2-b]pyridin-5-yl)methyl]amino}pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate

tert-Butyl((3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(Prepared in Intermediate 1, Step 11; 120 mg, 0.27 mmol) and3-bromofuro[3,2-b]pyridine-5-carbaldehyde (68 mg, 0.30 mmol) weredissolved in toluene (6.0 mL). Then catalytic amount of acetic acid wasadded and the reaction mixture was heated at 100° C. for 2 h. After thistime, the reaction mixture was cooled to room temperature and toluenewas evaporated under reduced pressure. The resulting intermediate iminewas dissolved in methanol (5.0 mL) and resulting reaction mixture wascooled to 0° C. Then sodium tetrahydroborate (26 mg, 0.69 mmol) wasslowly added and the reaction mixture was stirred at room temperaturefor 30 min. After this time, water was added to the reaction mixture andproduct was extracted with EtOAc. Combined organic fractions were washedwith brine, dried over Na₂SO₄ and solvents were evaporated under reducedpressure. The crude product was purified by Biotage Isolera to give thedesired compound (420 mg, 68%). LCMS calc. for C₃₀H₄₅BrN₅O₄Si (M+H)⁺m/z=646.2. found: 646.2.

Intermediate 5 tert-Butyl[(3S,5R)-1-(3-{[(3-bromofuro[3,2-b]pyridin-5-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate

tert-Butyl[(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(Prepared in Intermediate 2, Step 6; 84 mg, 0.27 mmol) and3-bromofuro[3,2-b]pyridine-5-carbaldehyde (Prepared in Intermediate 4,Step 8; 68 mg, 0.30 mmol) were dissolved in toluene (5 mL). Thencatalytic amount of acetic acid was added and the reaction mixture washeated at 100° C. for 2 h. After this time, the reaction mixture wascooled to room temperature and toluene was evaporated under reducedpressure. The resulting intermediate imine was dissolved in methanol (5mL) and resulting reaction mixture was cooled to 0° C. Then sodiumtetrahydroborate (26 mg, 0.69 mmol) was slowly added and the reactionmixture was stirred at room temperature for 30 min. After this time,water was added to the reaction mixture and product was extracted withEtOAc. Combined organic fractions were washed with brine, dried overNa₂SO₄ and solvents were evaporated under reduced pressure. The crudeproduct was purified by Biotage Isolera to give the desired compound (82mg, 58%). LCMS calc. for C₂₄H₃₁BrN₅O₃(M+H)⁺ m/z=516.2. found: 516.1.

Intermediate 6 tert-Butyl[(1S,3R,5S)-3-(3-aminopyridin-4-yl)-5-methylcyclohexyl]carbamate andtert-butyl[(1R,3S,5R)-3-(3-aminopyridin-4-yl)-5-methylcyclohexyl]carbamate

Step 1. 5-Methyl-3-oxocyclohex-1-en-1-yl trifluoromethanesulfonate

To a solution of 5-methylcyclohexane-1,3-dione (50.1 g, 397 mmol) in DCM(700 mL) was added Na₂CO₃ (46.3 g, 437 mmol) and the resulting mixturewas cooled to 0° C. A solution of trifluoromethanesulfonic anhydride(66.8 mL, 397 mmol) in DCM (600 mL) was added dropwise over 1 h at 0° C.The reaction mixture was stirred at room temperature for 2 h. Thesolution was filtered and the filtrate was quenched by careful additionof saturated aq. NaHCO₃ to pH=7. The organic layer was washed withwater, brine, dried over Na₂SO₄ and concentrated under reduced pressureto give the sub-title product as light yellow oil, which was used fornext step without further purification. LCMS calc. for C₈H₁₀F₃O₄S(M+H)⁺: m/z=259.0. Found: 259.1.

Step 2.5-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-en-1-one

To a mixture of4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl](77.6 g,306 mmol), potassium acetate (77.1 g, 785 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith DCM (1:1) (8.6 g, 10.0 mmol) under N₂ was added a solution of5-methyl-3-oxocyclohex-1-en-1-yl trifluoromethanesulfonate (67.6 g, 262mmol) in 1,4-dioxane (420 mL). The reaction mixture was degassed with N₂and the mixture was stirred at 80° C. overnight. After cooling to roomtemperature, the mixture was filtered through a pad of diatomaceousearth (eluted with EtOAc). The filtrate was concentrated under reducedpressure, and the crude product was used in next step without furtherpurification.

Step 3. 5-Methyl-3-(3-nitropyridin-4-yl)cyclohex-2-en-1-one

A solution of5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-en-1-one(20.0 g, 84.7 mmol) in 1,4-dioxane (120 mL), 4-chloro-3-nitropyridine(10.0 g, 63.1 mmol), 2.0 M Na₂Co₃ in water (63.1 mL, 126 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith DCM (1:1) (2.58 g, 3.15 mmol) was refluxed under a N₂ atmospherefor 1 h. The reaction mixture was diluted with EtOAc and water, thenfiltered through a pad of diatomaceous earth, and washed with EtOAc. Thetwo layers were separated, and the aqueous layer was extracted withEtOAc (2×). The combined organic phases were washed with water andbrine, and dried over Na₂SO₄. The crude residue was purified by flashchromatography (eluting with a gradient 0-60% EtOAc in hexanes) to givethe sub-title product as an orange oil (6.6 g, 45%). LCMS calc. forC₁₂H₁₃N₂O₃ (M+H)⁺: m/z=233.1. Found: 233.1.

Step 4. cis-(+/−)-5-Methyl-3-(3-nitropyridin-4-yl)cyclohex-2-en-1-ol

To a solution of 5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-en-1-one(6.6 g, 28 mmol) in EtOH (93 mL) was added CeCl₃.7H₂O (12.7 g, 34.1mmol), The resulting mixture was cooled to 0° C. and NaBH₄ (1.29 g, 34.1mmol) was added portion-wise. After stirring at 0° C. for 1 h, thereaction was quenched with water and concentrated under reduced pressureto remove the EtOH. The residue was then extracted with EtOAc. Theorganic layer was washed with brine, dried over Na₂SO₄, filtered, andconcentrated. The crude product was purified by flash chromatography(gradient elution with 20-90% EtOAc in hexanes) to give the sub-titleproduct as a racemic mixture (6.4 g, 96%). LCMS calc. for C₁₂H₁₅N₂O₃(M+H)⁺: m/z=235.1. Found: 235.1.

Step 5. 4-(3-(tert-Butyldimethylsilyloxy)-5-methylcyclohex-1-enyl)3-nitropyridine

A solution ofcis(+/−)-5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-en-1-ol (6.4 g, 27mmol) in DMF (51 mL) was added 1H-imidazole (3.7 g, 55 mmol) andtert-butyldimethylsilyl chloride (5.8 g, 38 mmol). The resulting mixturewas stirred at room temperature overnight. The reaction solution wasdiluted with water and EtOAc. The organic layer was washed with water(2×), brine, dried over Na₂SO₄ and concentrated under reduced pressureto give product as an orange oil. LCMS calc. for C₁₈H₂₉N₂O₃Si (M+H)⁺:m/z=349.2. Found: 349.2.

Step 6.4-(3-(tert-Butyldimethylsilyloxy)-5-methylcyclohex-1-enyl)pyridin-3-amine

A mixture of4-(3-(tert-butyldimethylsilyloxy)-5-methylcyclohex-1-enyl)₃-nitropyridine(9.3 g, 27 mmol), iron (8.9 g, 160 mmol) and AcOH (67 mL) was stirred atroom temperature for 2 h. The reaction mixture was filtered through apad of diatomaceous earth, washed with MeOH. The filtrate wasconcentrated under reduced pressure to remove the volatiles, the residuewas dissolved in EtOAc, washed with saturated aq. Na₂CO₃, washed withbrine, dried over Na₂SO₄, filtered, and concentrated under reducedpressure to give the sub-title product as a yellow oil (7.7 g, 90%).LCMS calc. for C₁₈H₃₁N₂OSi (M+H)⁺: m/z=319.2. Found: 319.2.

Step 7.4-(3-(tert-Butyldimethylsilyloxy)-5-methylcyclohexyl)pyridin-3-amine

To a suspension of4-(3-(tert-butyldimethylsilyloxy)-5-methylcyclohex-1-enyl)pyridin-3-amine(7.7 g, 24 mmol) in MeOH (203 mL) under N₂ was added 10% Pd on carbon(2.64 g). The mixture was purged with H₂ and stirred under a H₂ balloonfor 3 h. The mixture was filtered through a pad of diatomaceous earthand eluted with MeOH. The filtrate was concentrated under reducedpressure to give the crude product as an off-white foamy solid (7.3 g,93%). The crude product was used directly in the next step withoutfurther purification. LCMS calc. for C₁₈H₃₃N₂OSi (M+H)⁺: m/z=321.2.Found: 321.3.

Step 8. cis (+/−) Benzyl4-(3-(tert-butyldimethylsilyloxy)-5-methylcyclohexylpyridin-3-ylcarbamate

To a solution of4-(3-(tert-butyldimethylsilyloxy)-5-methylcyclohexyl)pyridin-3-amine(7.3 g, 23 mmol) in DCM (50 mL) was addedN-(benzyloxycarbonyloxy)succinimide (6.5 g, 26 mmol) and DMAP (0.14 g,1.2 mmol). After stirring for 16 h, another portion ofN-(benzyloxycarbonyloxy)succinimide (3.1 g, 12 mmol) was added, followedby DMAP. The reaction mixture was stirred overnight. The reactionsolution was partitioned between EtOAc and saturated aq. Na₂CO₃solution. The organic layer was washed with saturated aq. Na₂CO₃solution and brine, dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by flash chromatography (gradient elution with0-40% EtOAc in hexanes) to give the sub-title product as a brown oil.LCMS calc. for C₂₆H₃₉N₂O₃Si (M+H)⁺: m/z=455.3. Found: 455.2.

Step 9. cis-(+/−)Benzyl4-(-3-hydroxy-5-methylcyclohexyl)pyridin-3-ylcarbamate

To a solution of cis (+/−) benzyl4-3-(tert-butyldimethylsilyloxy)-5-methylcyclohexylpyridin-3-ylcarbamate(7.0 g, 15 mmol) in MeOH (100.0 mL) was added 6.0 M HCl in water (50.0mL, 300 mmol). The resulting mixture was stirred at room temperature for6 h. The pH was then adjusted to pH=7 by addition of 6 N NaOH and thevolatiles were removed under reduced pressure. The aqueous layer wasextracted with EtOAc and the organic was washed with brine, dried overMgSO₄, filtered and concentrated under reduced pressure to give thecrude product which was used in next step without purification (4.8 g,92%). LCMS calc. for C₂₀H₂₅N₂O₃ (M+H)⁺: m/z=341.2. Found: 341.1.

Step 10. cis-(+/−)-Benzyl4-(3-methyl-5-oxocyclohexyl)pyridin-3-ylcarbamate

To a solution of cis-(+/−)benzyl4-(-3-hydroxy-5-methylcyclohexyl)pyridin-3-ylcarbamate (4.8 g, 14 mmol)in DCM (90 mL) was added Dess-Martin periodinane (8.97 g, 21.2 mmol).The reaction mixture was stirred at room temperature for 2 h. Thereaction mixture was diluted with Et₂O and saturated aq. NaHCO₃ solutionand stirred for 30 min. The organic layer was separated and washed withbrine, dried over Na₂SO₄, filtered and concentrated. The crude productwas purified by flash chromatography (gradient elution with 0-50% EtOAcin hexanes) to give the sub-title product (2.5 g, 52%). LCMS calc. forC₂₀H₂₃N₂O₃ (M+H)⁺: m/z=339.2. Found: 339.1.

Step 11. cis-(+/−)-Benzyl4-(3-(benzylamino)-5-methylcyclohexyl)pyridin-3-ylcarbamate

To a solution of cis-(+/−)-benzyl4-(3-methyl-5-oxocyclohexyl)pyridin-3-ylcarbamate (2.50 g, 7.39 mmol) inMeOH (30 mL) was added benzylamine (2.42 mL, 22.2 mmol). The resultingmixture was stirred at room temperature for 2 h. After cooling to −78°C., 2.0 M LiBH₄ in THF (4.1 mL, 8.1 mmol) was added. The reactionmixture was warmed to room temperature and stirred overnight. Thesolution was partitioned between EtOAc and saturated aq. NaHCO₃, thenthe resulting layers were separated. The organic layer was washed withadditional saturated aq. NaHCO₃ and brine, dried over MgSO₄, filtered,and concentrated. The crude product was used in the next step withoutpurification (3.1 g, 98%). LCMS calc. for C₂₇H₃₂N₃O₂ (M+H)⁺: m/z=430.2.Found: 430.2.

Step 12. tert-Butyl[(1S,3R,5S)-3-(3-aminopyridin-4-yl)-5-methylcyclohexyl]carbamate andtert-Butyl[(1R,3S,5R)-3-(3-aminopyridin-4-yl)-5-methylcyclohexyl]carbamate

To a solution of cis-(+/−)-benzyl4-(3-(benzylamino)-5-methylcyclohexyl)pyridin-3-ylcarbamate (3.10 g,7.22 mmol) in MeOH (100 mL) was added 20% palladium hydroxide on carbon(1.0 g, 1.4 mmol). The resulting heterogeneous solution was put under anatmosphere of H₂ and was stirred for 14 h, at which time the reactionmixture was purged with N₂, di-tert-butyldicarbonate (1.6 g, 7.2 mmol)was added and the solution was stirred for 7 h. Additionaldi-tert-butyldicarbonate (1.6 g, 7.2 mmol) was added and the solutionwas stirred overnight. The solvent was removed under reduced pressureand the residue was purified by flash chromatography (gradient elutionwith 20-100% EtOAc in hexanes) to give the racemic product. The racemicmixture was separated by chiral column (CHIRALPAK® IA column elutingwith 15% EtOH/85% Hexanes, 12 mL/min) to give two peaks.

Peak 1 retention time 14.3 min., LCMS calc. for C₁₇H₂₈N₃O₂ (M+H)⁺:m/z=306.2. Found: 306.2.

Peak 2 retention time 18.6 min., LCMS calc. for C₁₇H₂₈N₃O₂ (M+H)⁺:m/z=306.2. Found: 306.2.

Peak 1 is tentatively identified as tert-butyl[(1R,3S,5R)-3-(3-aminopyridin-4-yl)-5-methylcyclohexyl]carbamate.

Peak 2 is tentatively identified as tert-butyl[(1S,3R,5S)-3-(3-aminopyridin-4-yl)-5-methylcyclohexyl]carbamate.

Example 1(3R,4R,5S)-3-Amino-1-{3-[({6-[2,6-difluoro-4-(3-hydroxytetrahydrofuran-3-yl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol

Step 1. 3-(3,5-Difluorophenyl)tetrahydrofuran-3-ol

Dihydrofuran-3(2H)-one (340 mg, 4.0 mmol) and a magnet bar were placedin a vial. The vial was evacuated and backfilled with nitrogen threetimes. After addition of tetrahydrofuran (6.0 mL), the reaction mixturewas cooled to 0° C. Then 0.5 M solution of (3,5-difluorophenyl)magnesiumbromide in THF (from Aldrich, 8.8 mL, 4.4 mmol) was slowly added and thereaction mixture was stirred at room temperature for 16 h. After thistime it was carefully quenched by the addition of the saturated solutionof ammonium chloride. The product was extracted with EtOAc. Combinedorganic fractions were washed with brine, dried over Na₂SO₄ and solventswere evaporated under reduced pressure. The resulting product was usedin the next step without further purification (448 mg, 56%).

Step 2.3-[3,5-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]tetrahydrofuran-3-ol

3-(3,5-Difluorophenyl)tetrahydrofuran-3-ol (448 mg, 2.24 mmol) and amagnet bar were placed in a vial. The vial was evacuated and backfilledwith nitrogen three times. After addition of tetrahydrofuran (9.0 mL),the reaction mixture was cooled to −78° C. Then 2.5 M solution ofn-butyllithium in hexanes (2.2 mL, 5.6 mmol) was slowly added and thereaction mixture was stirred at −78° C. for 1 h. After this time2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (from Aldrich, 1.37mL, 6.71 mmol) was slowly added. After stirring at −78° C. for 5 minmore, the reaction mixture was allowed to warm to room temperature andthe reaction mixture was stirred at room temperature for 1 h. After thistime it was carefully quenched by the addition of the saturated solutionof ammonium chloride. The product was extracted with EtOAc. Combinedorganic fractions were washed with brine, dried over Na₂SO₄ and solventswere evaporated under reduced pressure. The resulting product was usedin the next step without further purification (610 mg, 84%).

Step 3. tert-Butyl((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-{3-[({6-[2,6-difluoro-4-(3-hydroxytetrahydrofuran-3-yl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate

tert-Butyl((3R,4R,5S)-1-(3-{[(6-bromo-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(intermediate 1, 20.0 mg, 0.0320 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (2.5 mg, 0.0032 mmol), potassium phosphate (20 mg, 0.096mmol) and magnet bar were placed in a vial with septum. The vial wasthen evacuated and backfilled with nitrogen three times. 1,4-Dioxane(2.5 mL) and degassed water (0.3 mL) were added to the reaction mixtureto the reaction mixture. Finally3-[3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]tetrahydrofuran-3-ol(17 mg, 0.051 mmol) was added and the reaction mixture was stirred at65° C. for 1 h. Then the reaction mixture was diluted with EtOAc. Theresulting solution was washed with brine, dried over Na₂SO₄ and solventevaporated. The resulting crude product was used in the next stepwithout further purification. LCMS calc. for C₃₈H₅₃F₃N₅O₅Si (M+H)⁺m/z=744.4. found: 744.4.

Step 4.(3R,4R,5S)-3-Amino-1-{3-[({6-[2,6-difluoro-4-(3-hydroxytetrahydrofuran-3-yl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol

tert-Butyl((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-{3-[({6-[2,6-difluoro-4-(3-hydroxytetrahydrofuran-3-yl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate(24 mg, 0.032 mmol) was dissolved in methanol (2 mL). Then 4.0 Msolution of HCl in dioxane (1 mL, 4 mmol) was added to the reactionmixture to the reaction mixture. The resultant reaction mixture wasstirred at room temperature overnight. Then the reaction mixture wasneutralized by addition of the ammonia solution and purified by RP-HPLC(water XBridge C18 column, 30 mm×100 mm, 5 μm particle size, gradientelution with acetonitrile/water containing 0.1% NH₄OH, at flow rate of60 mL/min). LCMS calc. for C₂₇H₃₁F₃N₅O₃(M+H)⁺ m/z=530.2. found: 530.2.¹H NMR (400 MHz, DMSO-d6) δ 7.91 (t, J=9.0 Hz, 1H), 7.81 (d, J=5.1 Hz,1H), 7.77 (s, 1H), 7.58 (dd, J=8.7, 3.9 Hz, 1H), 7.38 (d, J=9.3 Hz, 2H),6.83 (d, J=5.1 Hz, 1H), 5.74 (br, 1H), 5.65 (t, J=5.7 Hz, 1H), 4.83 (br,1H), 4.53 (t, J=6.1 Hz, 2H), 4.04 (dd, J=9.0, 5.0 Hz, 2H), 3.88-3.77 (m,2H), 3.27-3.11 (m, 2H), 2.80-2.64 (m, 2H), 2.43-2.30 (m, 4H), 2.27-2.13(m, 2H), 0.85 (d, J=6.5 Hz, 3H) ppm.

Example 2(3R,4R,5S)-3-Amino-1-(3-(((6-(2,6-difluoro-4-(1-hydroxycyclobutyl)phenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol

This compound was synthesized using similar procedures as described inExample 1, using cyclobutanone to replace dihydrofuran-3(2H)-one inStep 1. LCMS calc. for C₂₇H₃₁F₃N₅O₂ (M+H)⁺ m/z=514.2. found: 514.2. ¹HNMR (400 MHz, DMSO-d6) δ 7.91 (t, J=9.0 Hz, 1H), 7.81 (d, J=5.1 Hz, 1H),7.76 (s, 1H), 7.57 (dd, J=8.6, 3.9 Hz, 1H), 7.34 (d, J=9.3 Hz, 2H), 6.83(d, J=5.1 Hz, 1H), 5.84 (s, 1H), 5.62 (t, J=5.6 Hz, 1H), 4.76 (d, J=4.7Hz, 1H), 4.53 (t, J=5.3 Hz, 2H), 3.27-3.13 (m, 3H), 2.80-2.62 (m, 3H),2.48-2.41 (m, 2H), 2.38-2.27 (m, 3H), 2.22 (t, J=11.5 Hz, 1H), 2.04-1.91(m, 1H), 1.85-1.61 (m, 2H), 0.86 (d, J=6.6 Hz, 3H) ppm.

Example 3(3R,4R,5S)-3-Amino-1-(3-(((6-(2,6-difluoro-4-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol

This compound was synthesized using similar procedures as described inExample 1, using dihydro-2H-pyran-4(3H)-one to replacedihydrofuran-3(2H)-one in Step 1. LCMS calc. for C₂₈H₃₃F₃N₅O₃(M+H)⁺m/z=544.3. found: 544.3. ¹H NMR (400 MHz, DMSO-d6) δ 7.91 (t, J=9.0 Hz,1H), 7.81 (d, J=5.1 Hz, 1H), 7.77 (s, 1H), 7.57 (dd, J=8.7, 3.8 Hz, 1H),7.37 (d, J=9.5 Hz, 2H), 6.83 (d, J=5.1 Hz, 1H), 5.63 (t, J=5.7 Hz, 1H),5.37 (s, 1H), 4.79 (d, J=4.6 Hz, 1H), 4.53 (t, J=5.5 Hz, 2H), 3.86-3.69(m, 3H), 3.20 (t, J=14.0 Hz, 1H), 2.79-2.63 (m, 2H), 2.39-2.30 (m, 2H),2.22 (t, J=11.5 Hz, 2H), 2.13-1.99 (m, 2H), 1.79-1.65 (m, 1H), 1.57 (d,J=13.2 Hz, 2H), 0.86 (d, J=6.6 Hz, 3H) ppm.

Example 43-(4-{6-[({4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)tetrahydrofuran-3-ol

Step 1. tert-Butyl((3S,5R)-1-{3-[({6-[2,6-difluoro-4-(3-hydroxytetrahydrofuran-3-yl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate

tert-Butyl[(3S,5R)-1-(3-{[(6-bromo-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(intermediate 2, 15.8 mg, 0.0320 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (2.5 mg, 0.0032 mmol), potassium phosphate (20 mg, 0.096mmol) and magnet bar were placed in a vial with septum. The vial wasthen evacuated and backfilled with nitrogen three times. 1,4-Dioxane(2.5 mL) and degassed water (0.3 mL) were added to the reaction mixture.Finally3-[3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]tetrahydrofuran-3-ol(Example 1, Step 2; 17 mg, 0.051 mmol) was added and the reactionmixture was stirred at 65° C. for 1 h. Then the reaction mixture wasdiluted with EtOAc. The resulting solution was washed with brine, driedover Na₂SO₄ and solvent evaporated. The resulting crude product was usedin the next step without further purification. LCMS calc. forC₃₂H₃₉F₃N₅O₄(M+H)⁺ m/z=614.3. found: 614.3.

Step 2.3-(4-{6-[({4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)tetrahydrofuran-3-ol

tert-Butyl((3S,5R)-1-{3-[({6-[2,6-difluoro-4-(3-hydroxytetrahydrofuran-3-yl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate(20 mg, 0.032 mmol) was dissolved in methanol (2 mL). Then 4.0 Msolution of HCl in dioxane (1 mL, 4 mmol) was added to the reactionmixture. The reaction mixture was stirred at room temperature overnight.Then the reaction mixture was neutralized by addition of the ammoniasolution and purified by RP-HPLC (water XBridge C18 column, 30 mm×100mm, 5 m particle size, gradient elution with acetonitrile/watercontaining 0.1% NH₄OH, at flow rate of 60 mL/min). LCMS calc. forC₂₇H₃₁F₃N₅O₂(M+H)⁺ m/z=514.2. found: 514.2. ¹H NMR (400 MHz, DMSO-d6) δ7.93 (t, J=8.9 Hz, 1H), 7.85 (d, J=5.0 Hz, 1H), 7.81 (s, 1H), 7.61 (dd,J=8.7, 3.9 Hz, 1H), 7.41 (d, J=9.4 Hz, 2H), 6.86 (d, J=5.1 Hz, 1H),5.83-5.73 (m, 2H), 4.63-4.45 (m, 2H), 4.06 (dd, J=8.9, 5.0 Hz, 3H),3.87-3.80 (m, 1H), 3.20-3.09 (m, 1H), 2.43-2.28 (m, 3H), 2.24-2.13 (m,1H), 2.06 (t, J=11.2 Hz, 2H), 1.98-1.87 (m, 1H), 1.85-1.72 (m, 1H), 0.94(q, J=11.7 Hz, 1H), 0.79 (d, J=6.5 Hz, 3H) ppm.

Example 51-(4-(6-((4-((3S,5R)-3-Amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-3,5-difluorophenyl)cyclobutanol

This compound was synthesized using similar procedures as described inExample 4, using 0.5 M solution of (3,5-difluorophenyl)magnesium bromidein THF and cyclobutanone. LCMS calc. for C₂₇H₃₁F₃N₅O (M+H)⁺ m/z=498.3.found: 498.2. ¹H NMR (400 MHz, DMSO-d6) δ 7.93 (t, J=8.9 Hz, 1H), 7.82(d, J=5.0 Hz, 1H), 7.81 (s, 1H), 7.60 (dd, J=8.7, 3.9 Hz, 1H), 7.36 (d,J=9.4 Hz, 2H), 6.82 (d, J=5.1 Hz, 1H), 6.00-5.84 (m, 1H), 5.73 (t, J=5.3Hz, 1H), 4.52 (qd, J=16.4, 5.2 Hz, 2H), 3.22-3.08 (m, 2H), 2.84-2.71 (m,1H), 2.49-2.41 (m, 2H), 2.38-2.27 (m, 3H), 2.13 (t, J=10.6 Hz, 1H),2.03-1.92 (m, 2H), 1.86-1.58 (m, 3H), 0.78-0.65 (m, 4H) ppm.

Example 64-(4-(6-((4-((3S,5R)-3-Amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-3,5-difluorophenyl)tetrahydro-2H-pyran-4-ol

This compound was synthesized using similar procedures as described inExample 4, using 0.5 M solution of (3,5-difluorophenyl)magnesium bromidein THF and dihydro-2H-pyran-4(3H)-one. LCMS calc. for C₂₈H₃₃F₃N₅O₂(M+H)⁺m/z=528.3. found: 528.3. ¹H NMR (400 MHz, DMSO-d6) δ 7.93 (t, J=8.9 Hz,1H), 7.83 (d, J=5.0 Hz, 1H), 7.81 (s, 1H), 7.60 (dd, J=8.7, 3.8 Hz, 1H),7.39 (d, J=9.5 Hz, 2H), 6.82 (d, J=5.1 Hz, 1H), 5.73 (t, J=5.3 Hz, 2H),5.45 (s, 1H), 4.52 (qd, J=16.3, 4.9 Hz, 2H), 3.88-3.69 (m, 4H),3.24-3.09 (m, 2H), 2.91-2.75 (m, 1H), 2.17 (t, J=10.5 Hz, 2H), 2.14-2.00(m, 1H), 1.96 (t, J=11.2 Hz, 1H), 1.85-1.67 (m, 2H), 1.57 (d, J=13.1 Hz,2H), 0.74 (d, J=6.5 Hz, 3H) ppm.

Example 71-(4-{6-[({4-[(3S,5R)-3-Amino-5-(trifluoromethyl)piperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)cyclobutanol

Step 1. 1-(3,5-Difluorophenyl)cyclobutanol

Cyclobutanone (280 mg, 4.0 mmol) and a magnet bar were placed in a vial.The vial was evacuated and backfilled with nitrogen three times. Afteraddition of tetrahydrofuran (6.0 mL), the reaction mixture was cooled to0° C. Then 0.5 M solution of (3,5-difluorophenyl)magnesium bromide inTHF (8.8 mL, 4.4 mmol) was slowly added and the reaction mixture wasstirred at room temperature for 16 h. After this time it was carefullyquenched by the addition of saturated solution of ammonium chloride. Theproduct was extracted with EtOAc. Combined organic fractions were washedwith brine, dried over Na₂SO₄ and solvents were evaporated under reducedpressure. The resulting product was used in the next step withoutfurther purification (643 mg, 87%).

Step 2.1-[3,5-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclobutanol

1-(3,5-difluorophenyl)cyclobutanol (643 mg, 3.49 mmol) and a magnet barwere placed in a vial. The vial was evacuated and backfilled withnitrogen three times. After addition of tetrahydrofuran (14 mL), thereaction mixture was cooled to −78° C. Then 2.5 M solution ofn-butyllithium in hexanes (3.5 mL, 8.7 mmol) was slowly added and thereaction was stirred at −78° C. for 1 h. After this time2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.14 mL, 10.5mmol) was slowly added. After stirring at −78° C. for 5 min more, thereaction mixture was allowed to warm to room temperature and it wasstirred at room temperature for 1 h. After this time it was carefullyquenched by the addition of saturated solution of ammonium chloride. Theproduct was extracted with EtOAc. Combined organic fractions were washedwith brine, dried over Na₂SO₄ and solvents were evaporated under reducedpressure. The resulting product was used in the next step withoutfurther purification (660 mg, 61%).

Step 3. tert-Butyl[(3S,5R)-1-{3-[({6-[2,6-difluoro-4-(1-hydroxycyclobutyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-(trifluoromethyl)piperidin-3-yl]carbamate

tert-butyl((3S,5R)-1-(3-(((6-bromo-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl)carbamate(intermediate 3, 18 mg, 0.0320 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (2.5 mg, 0.0032 mmol), potassium phosphate (20 mg, 0.096mmol) and magnet bar were placed in a vial with septum. The vial wasthen evacuated and backfilled with nitrogen three times. 1,4-Dioxane(2.5 mL) and degassed water (0.3 mL) were added to the reaction mixtureto the reaction mixture. Finally1-[3,5-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclobutanol(16 mg, 0.051 mmol) was added and the reaction mixture was stirred at65° C. for 1 h. Then the reaction mixture was diluted with EtOAc. Theresulting solution was washed with brine, dried over Na₂SO₄ and solventevaporated. The resulting crude product was used in the next stepwithout further purification. LCMS calc. for C₃₂H₃₆F₆N₅O₃(M+H)⁺m/z=652.3. found: 652.3.

Step 4.1-(4-{6-[({4-[(3S,5R)-3-Amino-5-(trifluoromethyl)piperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)cyclobutanol

tert-Butyl[(3S,5R)-1-{3-[({6-[2,6-difluoro-4-(1-hydroxycyclobutyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-(trifluoromethyl)piperidin-3-yl]carbamate(21 mg, 0.032 mmol) was dissolved in methanol (2 mL). Then 4.0 Msolution of HCl in dioxane (1 mL, 4 mmol) was added to the reactionmixture. The reaction mixture was stirred at room temperature overnight.Then the reaction mixture was neutralized by addition of the ammoniasolution and purified by RP-HPLC (water XBridge C18 column, 30 mm×100mm, 5 m particle size, gradient elution with acetonitrile/watercontaining 0.1% NH₄OH, at flow rate of 60 mL/min). LCMS calc. forC₂₇H₂₈F₆N₅O (M+H)⁺ m/z=552.2. found: 552.3. ¹H NMR (400 MHz, DMSO-d6) δ7.93 (t, J=9.0 Hz, 1H), 7.85 (d, J=5.0 Hz, 1H), 7.83 (s, 1H), 7.58 (dd,J=8.7, 3.9 Hz, 1H), 7.35 (d, J=9.3 Hz, 2H), 6.91 (d, J=5.1 Hz, 1H), 5.86(dd, J=12.4, 6.8 Hz, 2H), 4.62-4.41 (m, 2H), 3.46-3.34 (m, 2H), 3.19(dd, J=10.9, 4.0 Hz, 2H), 2.91-2.78 (m, 1H), 2.78-2.64 (m, 1H),2.49-2.40 (m, 2H), 2.40-2.26 (m, 3H), 2.06-1.92 (m, 2H), 1.79 (dq,J=9.7, 8.2, 7.5 Hz, 1H), 1.75-1.60 (m, 1H), 1.14 (q, J=12.2 Hz, 1H) ppm.

Example 8(3R,4R,5S)-3-Amino-1-{3-[({6-[2,6-difluoro-4-(1-hydroxycyclopropyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol

Step 1. {[1-(3,5-Difluorophenyl)vinyl]oxy}(trimethyl)silane

To a solution of 1-(3,5-difluorophenyl)ethanone (Matrix Scientific, 500mg, 3.2 mmol) in DCM (13 mL) was added triethylamine (890 μL, 6.4 mmol).Then trimethylsilyl trifluoromethanesulfonate (from Aldrich, 640 μL, 3.5mmol) was slowly added at 0° C. to the resulting mixture. The reactionmixture was stirred at 0° C. for 15 min before it was carefully quenchedby the addition saturated aq. NaHCO₃. The product was extracted withEtOAc. Combined organic fractions were washed with brine, dried overNa₂SO₄ and solvents were evaporated under reduced pressure. Theresulting product was used in the next step without further purification(664 mg, 91%).

Step 2. {[1-(3,5-Difluorophenyl)cyclopropyl]oxy}(trimethyl)silane

To a solution of diiodomethane (2.5 g, 9.3 mmol) in DCM (30 mL) wasslowly added 1.2 M solution of diethyl zinc in toluene (7.8 mL, 9.3mmol) at 0° C. After stirring for 20 min at 0° C.,{[1-(3,5-difluorophenyl)vinyl]oxy}(trimethyl)silane (664 mg, 2.91 mmol)was added dropwise and the reaction mixture was stirred at roomtemperature overnight. After this time it was carefully quenched by theaddition of the saturated solution of ammonium chloride. The product wasextracted with DCM. Combined organic fractions were washed with brine,dried over Na₂SO₄ and solvents were evaporated under reduced pressure.The resulting product was used in the next step without furtherpurification (656 mg, 93%).

Step 3.1-(3,5-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanol

{[1-(3,5-Difluorophenyl)cyclopropyl]oxy}(trimethyl)silane (656 mg, 2.71mmol) and a magnet bar were placed in a vial. The vial was evacuated andbackfilled with nitrogen three times. After addition of tetrahydrofuran(12 mL), the reaction mixture was cooled to −78° C. Then 2.5 M solutionof n-butyllithium in hexanes (2.7 mL, 6.8 mmol) was slowly added and thereaction mixture was stirred at −78° C. for 1 h. After this time2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.66 mL, 8.12mmol) was slowly added. After stirring at −78° C. for 5 min, thereaction was allowed to warm to room temperature and it was stirred atroom temperature for 1 h. After this time the reaction mixture wascarefully quenched by the addition of the saturated solution of ammoniumchloride. The product was extracted with EtOAc. Combined organicfractions were washed with brine, dried over Na₂SO₄ and solvents wereevaporated under reduced pressure. The resulting product was used in thenext step without further purification (420 mg, 52%). LCMS calc. forC₁₅H₂₀BF₂O₃(M+H)⁺ m/z=297.1. found: 297.1.

Step 4. tert-Butyl((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-{3-[({6-[2,6-difluoro-4-(1-hydroxycyclopropyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate

tert-Butyl((3R,4R,5S)-1-(3-{[(6-bromo-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(intermediate 1, 20.0 mg, 0.0320 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (2.5 mg, 0.0032 mmol), potassium phosphate (20 mg, 0.096mmol) and magnet bar were placed in a vial with septum. The vial wasthen evacuated and backfilled with nitrogen three times. 1,4-Dioxane(2.5 mL) and degassed water (0.3 mL) were added to the reaction mixtureto the reaction mixture. Finally1-[3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropanol(15 mg, 0.051 mmol) was added and the reaction mixture was stirred at65° C. for 1 h. Then the reaction mixture was diluted with EtOAc. Theresulting solution was washed with brine, dried over Na₂SO₄ and solventevaporated. The resulting crude product was used in the next stepwithout further purification. LCMS calc. for C₃₇H₅₁F₃N₅O₄Si (M+H)⁺m/z=714.4. found: 714.3.

Step 5.(3R,4R,5S)-3-Amino-1-{3-[({6-[2,6-difluoro-4-(1-hydroxycyclopropyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol

tert-Butyl((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-{3-[({6-[2,6-difluoro-4-(1-hydroxycyclopropyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate(23 mg, 0.032 mmol) was dissolved in methanol (2 mL). Then 4.0 Msolution of HCl in dioxane (1 mL, 4 mmol) was added to the reactionmixture to the reaction mixture. The reaction mixture was stirred atroom temperature overnight. Then the reaction mixture was neutralized byaddition of the ammonia solution and purified by RP-HPLC (water XBridgeC18 column, 30 mm×100 mm, 5 μm particle size, gradient elution withacetonitrile/water containing 0.1% NH₄OH, at flow rate of 60 mL/min).LCMS calc. for C₂₆H₂₉F₃N₅O₂(M+H)⁺ m/z=500.2. found: 500.2.

Example 9(3R,4R,5S)-3-Amino-1-(3-(((6-(2,6-difluoro-3-(1-hydroxycyclopropyl)phenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol

This compound was synthesized according to the procedures described inExample 8, using 1-(2,4-difluorophenyl)ethanone to replace1-(3,5-difluorophenyl)ethanone in Step 1. LCMS calc. forC₂₆H₂₉F₃N₅O₂(M+H)⁺ m/z=500.2. found: 500.2.

Example 101-(4-{6-[({4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)cyclopropanol

Step 1. tert-Butyl((3S,5R)-1-{3-[({6-[2,6-difluoro-4-(1-hydroxycyclopropyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate

tert-Butyl[(3S,5R)-1-(3-{[(6-bromo-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(Intermediate 2, 15.8 mg, 0.0320 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (2.5 mg, 0.0032 mmol), potassium phosphate (20 mg, 0.096mmol) and magnet bar were placed in a vial with septum. The vial wasthen evacuated and backfilled with nitrogen three times. 1,4-Dioxane(2.5 mL) and degassed water (0.3 mL) were added to the reaction mixtureto the reaction mixture. Finally1-[3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropanol(Example 8, Step 3; 15 mg, 0.051 mmol) was added and the reactionmixture was stirred at 65° C. for 1 h. Then the reaction mixture wasdiluted with EtOAc. The resulting solution was washed with brine, driedover Na₂SO₄ and solvent evaporated. The resulting crude product was usedin the next step without further purification. LCMS calc. forC₃₁H₃₇F₃N₅O₃(M+H)⁺ m/z=584.3. found: 584.2.

Step 2.1-(4-{6-[({4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)cyclopropanol

tert-Butyl((3S,5R)-1-{3-[({6-[2,6-difluoro-4-(1-hydroxycyclopropyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate(19 mg, 0.032 mmol) was dissolved in methanol (2 mL). Then 4.0 Msolution of HCl in dioxane (1 mL, 4 mmol) was added to the reactionmixture. The reaction mixture was stirred at room temperature overnight.Then the reaction mixture was neutralized by addition of the ammoniasolution and purified by RP-HPLC (water XBridge C18 column, 30 mm×100mm, 5 μm particle size, gradient elution with acetonitrile/watercontaining 0.1% NH₄OH, at flow rate of 60 mL/min). LCMS calc. forC₂₆H₂₉F₃N₅O (M+H)⁺ m/z=484.2. found: 484.2. ¹H NMR (400 MHz, DMSO-d6) δ7.91 (t, J=9.0 Hz, 1H), 7.84 (d, J=5.0 Hz, 1H), 7.80 (s, 1H), 7.58 (dd,J=8.7, 3.8 Hz, 1H), 7.10 (d, J=9.6 Hz, 2H), 6.85 (d, J=5.1 Hz, 1H), 5.76(t, J=5.3 Hz, 2H), 4.62-4.45 (m, 3H), 3.21-3.05 (m, 1H), 2.32 (t, J=10.8Hz, 1H), 2.06 (t, J=11.3 Hz, 1H), 1.98-1.87 (m, 1H), 1.79 (br, 1H),1.30-1.20 (m, 2H), 1.19-1.09 (m, 2H), 0.92 (q, J=11.8 Hz, 1H), 0.80 (d,J=6.6 Hz, 3H) ppm.

Example 111-(3-(6-((4-((3S,5R)-3-Amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-2,4-difluorophenyl)cyclopropanol

This compound was synthesized according to the procedures described inExample 10, using 1-(2,4-difluorophenyl)ethanone. LCMS calc. forC₂₆H₂₉F₃N₅O (M+H)⁺ m/z=484.2. found: 484.2.

Example 12(3R,4R,5S)-3-Amino-1-{3-[({6-[2,6-difluoro-4-(2-hydroxy-2-methylpropyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol

Step 1. Methyl (3,5-difluorophenyl)acetate

(3,5-Difluorophenyl)acetic acid (Sigma-Aldrich, 690 mg, 4.0 mmol) andpotassium carbonate (1.1 g, 8.0 mmol) were added to DMF (12 mL). Aftersubsequent addition of methyl iodide (750 μL, 12 mmol), the resultantreaction mixture was stirred at room temperature for 6 h. After thistime, water was added to the reaction mixture and the product wasextracted with EtOAc. Combined organic fractions were washed with brine,dried over Na₂SO₄ and solvents were evaporated under reduced pressure.The crude product was purified by Biotage Isolera to give the desiredcompound (670 mg, 90%).

Step 2. 1-(3,5-Difluorophenyl)-2-methylpropan-2-ol

Methyl (3,5-difluorophenyl)acetate (670 mg, 3.6 mmol) and a magnet barwere placed in a vial. The vial was evacuated and backfilled withnitrogen three times. After addition of tetrahydrofuran (10 mL), thereaction mixture was cooled to 0° C. Then 3.0 M solution ofmethylmagnesium bromide in ether (3.6 mL, 11 mmol) was slowly added andthe reaction mixture was stirred at room temperature for 16 h. Afterthis time the reaction mixture was carefully quenched by the addition ofthe saturated solution of ammonium chloride. The product was extractedwith EtOAc. Combined organic fractions were washed with brine, driedover Na₂SO₄ and solvents were evaporated under reduced pressure. Theresulting product was used in the next step without further purification(301 mg, 45%).

Step 3.1-[3,5-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-methylpropan-2-ol

1-(3,5-Difluorophenyl)-2-methylpropan-2-ol (301 mg, 1.62 mmol) and amagnet bar were placed in a vial. The vial was evacuated and backfilledwith nitrogen three times. After addition of tetrahydrofuran (6.0 mL),the reaction mixture was cooled to −78° C. Then 2.5 M solution ofn-butyllithium in hexanes (1.6 mL, 4.0 mmol) was slowly added and thereaction was stirred at −78° C. for 1 h. After this time2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (989 μL, 4.85 mmol)was slowly added. After stirring at −78° C. for 5 min, the reactionmixture was allowed to warm to room temperature and it was stirred atroom temperature for 1 h. After this time the reaction mixture wascarefully quenched by the addition of saturated solution of ammoniumchloride. The product was extracted with EtOAc. Combined organicfractions were washed with brine, dried over Na₂SO₄ and solvents wereevaporated under reduced pressure. The resulting product was used in thenext step without further purification (343 mg, 68%).

Step 4. tert-Butyl((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-{3-[({6-[2,6-difluoro-4-(2-hydroxy-2-methylpropyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate

tert-Butyl((3R,4R,5S)-1-(3-{[(6-bromo-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(intermediate 1, 20.0 mg, 0.0320 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (2.5 mg, 0.0032 mmol), potassium phosphate (20 mg, 0.096mmol) and magnet bar were placed in a vial with septum. The vial wasthen evacuated and backfilled with nitrogen three times. 1,4-Dioxane(2.5 mL) and degassed water (0.3 mL) were added to the reaction mixtureto the reaction mixture. Finally1-[3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-methylpropan-2-ol(16 mg, 0.051 mmol) was added and the reaction mixture was stirred at65° C. for 1 h. Then the reaction mixture was diluted with EtOAc. Theresulting solution was washed with brine, dried over Na₂SO₄ and solventevaporated. The resulting crude product was used in the next stepwithout further purification. LCMS calc. for C₃₈H₅₅F₃N₅O₄Si (M+H)⁺m/z=730.4. found: 730.4.

Step 5.(3R,4R,5S)-3-Amino-1-{3-[({6-[2,6-difluoro-4-(2-hydroxy-2-methylpropyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol

tert-Butyl((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-{3-[({6-[2,6-difluoro-4-(2-hydroxy-2-methylpropyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate(23 mg, 0.032 mmol) was dissolved in methanol (2 mL). Then 4.0 Msolution of HCl in dioxane (1 mL, 4 mmol) was added to the reactionmixture. The reaction mixture was stirred at room temperature overnight.Then the reaction mixture was neutralized by addition of the ammoniasolution and purified by RP-HPLC (water XBridge C18 column, 30 mm×100mm, 5 μm particle size, gradient elution with acetonitrile/watercontaining 0.1% NH₄OH, at flow rate of 60 mL/min). LCMS calc. forC₂₇H₃₃F₃N₅O₂(M+H)⁺ m/z=516.3. found: 516.3. ¹H NMR (400 MHz, DMSO-d6) δ8.07 (d, J=6.1 Hz, 1H), 7.92 (t, J=8.9 Hz, 1H), 7.84 (s, 1H), 7.61 (dd,J=8.6, 3.8 Hz, 1H), 7.13 (s, 2H), 7.00 (s, 1H), 6.35 (s, 1H), 5.77 (s,1H), 4.61 (ddd, J=37.2, 16.7, 5.9 Hz, 3H), 3.91-3.77 (m, 1H), 3.58-3.45(m, 1H), 3.22-3.10 (m, 1H), 2.82-2.71 (m, 4H), 2.63-2.54 (m, 2H), 1.83(s, 1H), 1.13 (s, 6H), 0.95 (d, J=6.5 Hz, 3H) ppm.

Example 131-(4-{6-[({4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)-2-methylpropan-2-ol

Step 1. tert-Butyl((3S,5R)-1-{3-[({6-[2,6-difluoro-4-(2-hydroxy-2-methylpropyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate

tert-Butyl[(3S,5R)-1-(3-{[(6-bromo-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(Intermediate 2; 15.8 mg, 0.0320 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (2.5 mg, 0.0032 mmol), potassium phosphate (20 mg, 0.096mmol) and magnet bar were placed in a vial with septum. The vial wasthen evacuated and backfilled with nitrogen three times. 1,4-Dioxane(2.5 mL) and degassed water (0.3 mL) were added to the reaction mixtureto the reaction mixture. Finally1-[3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-methylpropan-2-ol(Example 12, Step 3; 16 mg, 0.051 mmol) was added and the reactionmixture was stirred at 65° C. for 1 h. Then the reaction mixture wasdiluted with EtOAc. The resulting solution was washed with brine, driedover Na₂SO₄ and solvent evaporated. The resulting crude product was usedin the next step without further purification. LCMS calc. forC₃₂H₄₁F₃N₅O₃(M+H)⁺ m/z=600.3. found: 600.3.

Step 2.1-(4-{6-[({4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)-2-methylpropan-2-ol

tert-Butyl((3S,5R)-1-{3-[({6-[2,6-difluoro-4-(2-hydroxy-2-methylpropyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate(19 mg, 0.032 mmol) was dissolved in methanol (2 mL). Then 4.0 Msolution of HCl in dioxane (1 mL, 4 mmol) was added to the reactionmixture to the reaction mixture. The reaction mixture was stirred atroom temperature overnight. Then the reaction mixture was neutralized byaddition of the ammonia solution and purified by RP-HPLC (water XBridgeC18 column, 30 mm×100 mm, 5 μm particle size, gradient elution withacetonitrile/water containing 0.1% NH₄OH, at flow rate of 60 mL/min).LCMS calc. for C₂₇H₃₃F₃N₅O (M+H)⁺ m/z=500.3. found: 500.3. ¹H NMR (400MHz, DMSO-d6) δ 8.07 (d, J=6.2 Hz, 1H), 7.94 (t, J=8.9 Hz, 1H), 7.87 (s,1H), 7.62 (dd, J=8.6, 3.8 Hz, 1H), 7.23 (s, 2H), 7.14 (d, J=9.2 Hz, 1H),6.24 (s, 1H), 4.73-4.48 (m, 3H), 3.73 (d, J=10.7 Hz, 1H), 3.47 (d,J=12.1 Hz, 1H), 2.77 (s, 2H), 2.64 (t, J=11.3 Hz, 2H), 2.39-2.26 (m,2H), 2.06 (d, J=12.1 Hz, 1H), 1.87 (s, 1H), 1.14 (d, J=2.5 Hz, 6H), 0.85(d, J=6.6 Hz, 3H) ppm.

Example 14(3R,4R,5S)-3-Amino-1-[3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-4-ol

Step 1. tert-Butyl{(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-[3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-3-yl}carbamate

tert-Butyl((3R,4R,5S)-1-(3-{[(6-bromo-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(intermediate 1, 20.0 mg, 0.0320 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (2.5 mg, 0.0032 mmol), potassium phosphate (20 mg, 0.096mmol) and magnet bar were placed in a vial with septum. The vial wasthen evacuated and backfilled with nitrogen three times. 1,4-Dioxane(2.5 mL) and degassed water (0.3 mL) were added to the reaction mixtureto the reaction mixture. Finally 2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (from Combi-Blocks, 13 mg, 0.051mmol) was added and the reaction mixture was stirred at 65° C. for 1 h.Then the reaction mixture was diluted with EtOAc. The resulting solutionwas washed with brine, dried over Na₂SO₄ and solvent evaporated. Theresulting crude product was used in the next step without furtherpurification. LCMS calc. for C₃₄H₄₇F₃N₅O₃Si (M+H)⁺ m/z=658.3. found:658.3.

Step 2.(3R,4R,5S)-3-Amino-1-[3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-4-ol

tert-Butyl{(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-[3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-3-yl}carbamate(21 mg, 0.032 mmol) was dissolved in methanol (2 mL). Then 4.0 Msolution of HCl in dioxane (1 mL, 4 mmol) was added to the reactionmixture to the reaction mixture. The reaction mixture was stirred atroom temperature overnight. Then the reaction mixture was neutralized byaddition of the ammonia solution and purified by RP-HPLC (water XBridgeC18 column, 30 mm×100 mm, 5 μm particle size, gradient elution withacetonitrile/water containing 0.1% NH₄OH, at flow rate of 60 mL/min).LCMS calc. for C₂₃H₂₅F₃N₅O (M+H)⁺ m/z=444.2. found: 444.2. ¹H NMR (400MHz, DMSO-d6) δ 7.89 (t, J=9.0 Hz, 1H), 7.79 (d, J=5.1 Hz, 1H), 7.74 (s,1H), 7.70-7.58 (m, 1H), 7.56 (dd, J=8.7, 3.9 Hz, 1H), 7.34-7.23 (m, 2H),6.82 (d, J=5.1 Hz, 1H), 5.63 (t, J=5.8 Hz, 1H), 4.61-4.45 (m, 3H),3.29-3.22 (m, 1H), 3.21-3.12 (m, 1H), 2.89-2.69 (m, 2H), 2.36 (t, J=10.7Hz, 1H), 2.23 (t, J=11.6 Hz, 1H), 1.79-1.63 (m, 1H), 0.87 (d, J=6.6 Hz,3H) ppm.

Example 15(3R,4R,5S)-3-Amino-1-(3-(((5-fluoro-6-(2-fluoro-6-methoxyphenyl)pyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol

This compound was synthesized according to the procedures described inExample 14, using 2-fluoro-6-methoxyphenylboronic acid (fromCombi-Blocks) to replace 2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in Step 1. LCMS calc. forC₂₄H₂₈F₂N₅O₂ (M+H)⁺ m/z=456.2. found: 456.4.

Example 16(3R,4R,5S)-3-Amino-5-methyl-1-(3-(((3,3′,5′-trifluoro-[2,4′-bipyridin]-6-yl)methyl)amino)pyridin-4-yl)piperidin-4-ol

This compound was synthesized according to the procedures described inExample 14, using 3,5-difluoropyridin-4-ylboronic acid (from Ark Pharm)to replace2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. LCMScalc. for C₂₂H₂₄F₃N₆O (M+H)⁺ m/z=445.2. found: 445.2.

Example 172-(6-((4-((3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-3-fluorobenzonitrile

This compound was synthesized using similar procedures as described inExample 14, using 2-cyano-6-fluorophenylboronic acid (from Combi-Blocks)to replace2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. LCMScalc. for C₂₄H₂₅F₂N₆O (M+H)⁺ m/z=451.2. found: 451.2.

Example 18(3R,4R,5S)-3-Amino-1-(3-(((5-fluoro-6-(2-fluorophenyl)pyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol

This compound was synthesized using similar procedures as described inExample 14, using 2-fluorophenylboronic acid (from Aldrich) to replace2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. LCMScalc. for C₂₃H₂₆F₂N₅O (M+H)⁺ m/z=426.2. found: 426.3.

Example 194-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-N-{[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}pyridin-3-amine

Step 1. tert-Butyl{(3S,5R)-1-[3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-3-yl}carbamate

tert-Butyl[(3S,5R)-1-(3-{[(6-bromo-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(intermediate 2, 15.8 mg, 0.0320 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (2.5 mg, 0.0032 mmol), potassium phosphate (20 mg, 0.096mmol) and magnet bar were placed in a vial with septum. The vial wasthen evacuated and backfilled with nitrogen three times. 1,4-Dioxane(2.5 mL) and degassed water (0.3 mL) were added to the reaction mixtureto the reaction mixture. Finally2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (13 mg,0.051 mmol) was added and the reaction mixture was stirred at 65° C. for1 h. Then the reaction mixture was diluted with EtOAc. The resultingsolution was washed with brine, dried over Na₂SO₄ and solventevaporated. The resulting crude product was used in the next stepwithout further purification. LCMS calc. for C₂₈H₃₃F₃N₅O₂(M+H)⁺m/z=528.3. found: 528.3.

Step 2.4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-{[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}pyridin-3-amine

tert-Butyl{(3S,5R)-1-[3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-3-yl}carbamate(17 mg, 0.032 mmol) was dissolved in methanol (2 mL). Then 4.0 Msolution of HCl in dioxane (1 mL, 4 mmol) was added to the reactionmixture.

The reaction mixture was stirred at room temperature overnight. Then thereaction mixture was neutralized by addition of the ammonia solution andpurified by RP-HPLC (water XBridge C18 column, 30 mm×100 mm, 5 μmparticle size, gradient elution with acetonitrile/water containing 0.1%NH₄OH, at flow rate of 60 mL/min). LCMS calc. for C₂₃H₂₅F₃N₅ (M+H)⁺m/z=428.2. found: 428.2.

Example 204-((3S,5R)-3-Amino-5-methylpiperidin-1-yl)-N-((5-fluoro-6-(2-fluoro-6-methoxyphenyl)pyridin-2-yl)methyl)pyridin-3-amine

This compound was synthesized using similar procedures as described inExample 19, using 2-fluoro-6-methoxyphenylboronic acid (fromCombi-Blocks) to replace2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. LCMScalc. for C₂₄H₂₈F₂N₅O (M+H)⁺ m/z=440.2. found: 440.2.

Example 214-((3S,5R)-3-Amino-5-methylpiperidin-1-yl)-N-((3,3′,5′-trifluoro-2,4′-bipyridin-6-yl)methyl)pyridin-3-amine

This compound was synthesized using similar procedures as described inExample 19, using 3,5-difluoropyridin-4-ylboronic acid (from Ark Pharm)to replace2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. LCMScalc. for C₂₂H₂₄F₃N₆ (M+H)⁺ m/z=429.2. found: 429.2.

Example 222-(6-((4-((3S,5R)-3-Amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-3-fluorobenzonitrile

This compound was synthesized using similar procedures as described inExample 19, using 2-cyano-6-fluorophenylboronic acid (from Combi-Blocks)to replace2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. LCMScalc. for C₂₄H₂₅F₂N₆ (M+H)⁺ m/z=435.2. found: 435.1.

Example 234-((3S,5R)-3-Amino-5-methylpiperidin-1-yl)-N-((5-fluoro-6-(2-fluorophenyl)pyridin-2-yl)methyl)pyridin-3-amine

This compound was synthesized using similar procedures as described inExample 19, using 2-fluorophenylboronic acid to replace2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. LCMScalc. for C₂₃H₂₆F₂N₅ (M+H)⁺ m/z=410.2. found: 410.2.

Example 242-(4-{6-[({4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)-2-methylpropanenitrile

Step 1. 2-(3,5-Difluorophenyl)-2-methylpropanenitrile

3,5-Difluorophenylacetonitrile (Sigma-Aldrich, 413 mg, 2.70 mmol) wasdissolved in DMF (8.0 mL) and the reaction mixture was cooled to 0° C.Then NaH in mineral oil (60%, 240 mg, 5.9 mmol) was slowly added to thereaction mixture. After addition was complete, the reaction mixture wasstirred at 0° C. for 30 min. Then methyl iodide (670 μL, 11 mmol) wasslowly added to the reaction mixture and the reaction mixture wasstirred at room temperature overnight. After this time, water was addedto the reaction mixture and the product was extracted with EtOAc.Combined organic fractions were washed with brine, dried over Na₂SO₄ andsolvents were evaporated under reduced pressure. The crude product waspurified by Biotage Isolera to give the desired compound (343 mg, 70%).

Step 2.2-[3,5-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-methylpropanenitrile

2-(3,5-Difluorophenyl)-2-methylpropanenitrile (343 mg, 1.89 mmol) and amagnet bar were placed in a vial. The vial was evacuated and backfilledwith nitrogen three times. After addition of tetrahydrofuran (6.0 mL),the reaction mixture was cooled to −78° C. Then 2.5M solution ofn-butyllithium in hexanes (1.5 mL, 3.8 mmol) was slowly added to thereaction mixture and the reaction mixture was stirred at −78° C. for 1h. After this time 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(960 μL, 4.7 mmol) was slowly added. After stirring at −78° C. for 5min, the reaction mixture was allowed to warm to room temperature andwas stirred at room temperature for 1 h. After this time the reactionmixture was carefully quenched by the addition of saturated solution ofammonium chloride. The product was extracted with EtOAc. Combinedorganic fractions were washed with brine, dried over Na₂SO₄ and solventswere evaporated under reduced pressure. The resulting product was usedin the next step without further purification.

Step 3. tert-Butyl((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-{3-[({6-[4-(1-cyano-1-methylethyl)-2,6-difluorophenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate

tert-Butyl((3R,4R,5S)-1-(3-{[(6-bromo-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(intermediate 1, 20.0 mg, 0.0320 mmol),bis(tri-t-butylphosphine)palladium (1.6 mg, 0.0031 mmol) and magnet barwere placed in a vial with septum. The vial was then evacuated andbackfilled with nitrogen three times. 1,4-Dioxane (2.5 mL), DIPEA (11μL, 0.062 mmol) and degassed water (0.3 mL) were added to the reactionmixture to the reaction mixture. Finally2-[3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-methylpropanenitrile(15 mg, 0.050 mmol) was added and the reaction mixture was stirred at70° C. for 1 h. Then the reaction mixture was diluted with EtOAc. Theresulting solution was washed with brine, dried over Na₂SO₄ and solventevaporated. The resulting crude product was used in the next stepwithout further purification. LCMS calc. for C₃₈H₅₂F₃N₆O₃Si (M+H)⁺m/z=725.4. found: 725.3.

Step 4.2-(4-{6-[({4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)-2-methylpropanenitrile

tert-Butyl((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-{3-[({6-[4-(1-cyano-1-methylethyl)-2,6-difluorophenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate(23 mg, 0.032 mmol) was dissolved in methanol (2 mL). Then 4.0 Msolution of HCl in dioxane (1 mL, 4 mmol) was added to the reactionmixture to the reaction mixture. The reaction mixture was stirred atroom temperature overnight. Then the reaction mixture was neutralized byaddition of the ammonia solution and purified by RP-HPLC (water XBridgeC18 column, 30 mm×100 mm, 5 μm particle size, gradient elution withacetonitrile/water containing 0.1% NH₄OH, at flow rate of 60 mL/min).LCMS calc. for C₂₇H₃₀F₃N₆O (M+H)⁺ m/z=511.2. found: 511.3. ¹H NMR (400MHz, DMSO-d6) δ 7.95 (t, J=9.0 Hz, 1H), 7.81 (d, J=5.1 Hz, 1H), 7.78 (s,1H), 7.61 (dd, J=8.7, 3.9 Hz, 1H), 7.48 (d, J=9.0 Hz, 2H), 6.83 (d,J=5.1 Hz, 1H), 5.66 (t, J=5.6 Hz, 1H), 4.76 (d, J=4.3 Hz, 1H), 4.62-4.44(m, 3H), 3.23-3.13 (m, 2H), 2.66 (d, J=6.5 Hz, 2H), 2.40-2.30 (m, 1H),2.20 (t, J=11.6 Hz, 1H), 1.78 (s, 6H), 1.66 (s, 1H), 0.83 (d, J=6.6 Hz,3H) ppm.

Example 24A2-(4-{6-[({4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)-2-methylpropanenitrile

Step 1. tert-Butyl((3S,5R)-1-{3-[({6-[4-(1-cyano-1-methylethyl)-2,6-difluorophenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate

tert-Butyl[(3S,5R)-1-(3-{[(6-bromo-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(intermediate 2, 15.3 mg, 0.0310 mmol),bis(tri-t-butylphosphine)palladium (1.6 mg, 0.0031 mmol) and magnet barwere placed in a vial with septum. The vial was then evacuated andbackfilled with nitrogen three times. 1,4-Dioxane (2.5 mL), DIPEA (11μL, 0.062 mmol) and degassed water (0.3 mL) were added to the reactionmixture to the reaction mixture. Finally2-[3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-methylpropanenitrile(Example 24, Step 2; 15 mg, 0.050 mmol) was added to the reactionmixture and the reaction mixture was stirred at 70° C. for 1 h. Then thereaction mixture was diluted with EtOAc. The resulting solution waswashed with brine, dried over Na₂SO₄ and solvent evaporated. Theresulting crude product was used in the next step without furtherpurification. LCMS calc. for C₃₂H₃₈F₃N₆O₂(M+H)⁺ m/z=595.3. found: 595.4.

Step 2.2-(4-{6-[({4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)-2-methylpropanenitrile

tert-Butyl((3S,5R)-1-{3-[({6-[4-(1-cyano-1-methylethyl)-2,6-difluorophenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate(19 mg, 0.032 mmol) was dissolved in methanol (2 mL). Then 4.0 Msolution of HCl in dioxane (1 mL, 4 mmol) was added to the reactionmixture to the reaction mixture. The reaction mixture was stirred atroom temperature overnight. Then the reaction mixture was neutralized byaddition of the ammonia solution and purified by RP-HPLC (water XBridgeC18 column, 30 mm×100 mm, 5 μm particle size, gradient elution withacetonitrile/water containing 0.1% NH₄OH, at flow rate of 60 mL/min).LCMS calc. for C₂₇H₃₀F₃N₆ (M+H)⁺ m/z=495.3. found: 495.3. ¹H NMR (400MHz, DMSO-d6) δ 7.96 (t, J=9.0 Hz, 1H), 7.83 (d, J=5.0 Hz, 1H), 7.81 (s,1H), 7.63 (dd, J=8.7, 3.9 Hz, 1H), 7.51 (d, J=9.1 Hz, 2H), 6.82 (d,J=5.1 Hz, 1H), 5.74 (t, J=5.3 Hz, 1H), 4.61-4.43 (m, 3H), 3.23-3.05 (m,2H), 2.77 (ddt, J=14.9, 8.5, 4.1 Hz, 2H), 2.14 (t, J=10.5 Hz, 1H), 1.96(t, J=11.1 Hz, 2H), 1.79 (d, J=1.6 Hz, 6H), 1.70 (s, 1H), 0.78-0.71 (m,3H) ppm.

Example 24B(3R,4R,5S)-3-Amino-5-methyl-1-(3-{[(2′,6,6′-trifluorobiphenyl-3-yl)methyl]amino}pyridin-4-yl)piperidin-4-ol

Step 1. tert-Butyl((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-{3-[(3-chloro-4-fluorobenzyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate

tert-Butyl((3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(Prepared in Intermediate 1, Step 11; 30.0 mg, 0.0687 mmol) and3-chloro-4-fluorobenzaldehyde (from Aldrich, 14 mg, 0.089 mmol) wereadded to toluene (3.0 mL). Then catalytic amount of acetic acid wasadded to the reaction mixture and the reaction mixture was heated at100° C. for 2 h. After this time, the reaction mixture was cooled toroom temperature and toluene was evaporated under reduced pressure. Theresulting intermediate imine was dissolved in methanol (5.0 mL) and thesolution was cooled to 0° C. Then sodium tetrahydroborate (6.5 mg, 0.17mmol) was slowly added to the reaction mixture and the reaction mixturewas stirred at room temperature for 30 min. After this time, water wasadded to the reaction mixture and product was extracted with EtOAc.Combined organic fractions were washed with brine, dried over Na₂SO₄ andsolvents were evaporated under reduced pressure. The crude product waspurified by Biotage Isolera to give the desired compound (40 mg, 99%).LCMS calc. for C₂₉H₄₅ClFN₄O₃Si (M+H)⁺ m/z=579.3. found: 579.3.

Step 2. tert-Butyl[(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methyl-1-(3-{[(2′,6,6′-trifluorobiphenyl-3-yl)methyl]amino}pyridin-4-yl)piperidin-3-yl]carbamate

tert-Butyl((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-{3-[(3-chloro-4-fluorobenzyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate(40.0 mg, 0.0690 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (5.0 mg, 0.0064 mmol), potassium phosphate (40 mg, 0.192mmol) and magnet bar were placed in a vial with septum. The vial wasthen evacuated and backfilled with nitrogen three times. 1,4-Dioxane(2.5 mL) and degassed water (0.3 mL) were added to the reaction mixtureto the reaction mixture. Finally2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (26 mg,0.11 mmol) was added and the reaction mixture was stirred at 65° C. for1 h. Then the reaction mixture was diluted with EtOAc. The resultingsolution was washed with brine, dried over Na₂SO₄ and solventevaporated. The resulting crude product was used in the next stepwithout further purification. LCMS calc. for C₃₅H₄₈F₃N₄O₃Si (M+H)⁺m/z=657.3. found: 657.3.

Step 3. (3R,4R,5S)-3-Amino-5-methyl-1-(3-{[(2′,6,6′-trifluorobiphenyl-3-yl)methyl]amino}pyridin-4-yl)piperidin-4-ol

tert-Butyl[(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methyl-1-(3-{[(2′,6,6′-trifluorobiphenyl-3-yl)methyl]amino}pyridin-4-yl)piperidin-3-yl]carbamate(21 mg, 0.032 mmol) was dissolved in methanol (2 mL). Then 4.0 Msolution of HCl in dioxane (1 mL, 4 mmol) was added to the reactionmixture to the reaction mixture. The reaction mixture was stirred atroom temperature overnight. Then the reaction mixture was neutralized byaddition of the ammonia solution and purified by RP-HPLC (water XBridgeC18 column, 30 mm×100 mm, 5 μm particle size, gradient elution withacetonitrile/water containing 0.1% NH₄OH, at flow rate of 60 mL/min).LCMS calc. for C₂₄H₂₆F₃N₄O (M+H)⁺ m/z=443.2. found: 443.2.

Example 254-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-N-[(2′,6,6′-trifluorobiphenyl-3-yl)methyl]pyridin-3-amine

Step 1. tert-Butyl((3S,5R)-1-{3-[(3-chloro-4-fluorobenzyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate

tert-Butyl[(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(Prepared in Intermediate 2, Step 6; 21.0 mg, 0.0687 mmol) and3-chloro-4-fluorobenzaldehyde (14 mg, 0.089 mmol) were added to toluene(3 mL). Then catalytic amount of acetic acid was added and the reactionmixture was heated at 100° C. for 2 h. After this time, the reactionmixture was cooled to room temperature and toluene was evaporated underreduced pressure. The resulting intermediate imine was dissolved inmethanol (3.0 mL) and the solution was cooled to 0° C. Then sodiumtetrahydroborate (6.5 mg, 0.17 mmol) was slowly added to the reactionmixture and the resultant reaction mixture was stirred at roomtemperature for 30 min. After this time, water was added to the reactionmixture and product was extracted with EtOAc. Combined organic fractionswere washed with brine, dried over Na₂SO₄ and solvents were evaporatedunder reduced pressure. The crude product was purified by BiotageIsolera to give the desired compound (30 mg, 99%). LCMS calc. forC₂₃H₃₁ClFN₄O₂ (M+H)⁺ m/z=449.2. found: 449.2.

Step 2. tert-Butyl[(3S,5R)-5-methyl-1-(3-{[(2′,6,6′-trifluorobiphenyl-3-yl)methyl]amino}pyridin-4-yl)piperidin-3-yl]carbamate

tert-Butyl((3S,5R)-1-{3-[(3-chloro-4-fluorobenzyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate(31.0 mg, 0.0690 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (5.0 mg, 0.0064 mmol), potassium phosphate (40 mg, 0.192mmol) and magnet bar were placed in a vial with septum. the vial wasthen evacuated and backfilled with nitrogen three times. 1,4-Dioxane(2.5 mL) and degassed water (0.3 mL) were added to the reaction mixtureto the reaction mixture. Finally2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (26 mg,0.11 mmol) was added to the reaction mixture and the reaction mixturewas stirred at 65° C. for 1 h. Then the reaction mixture was dilutedwith EtOAc. The resulting solution was washed with brine, dried overNa₂SO₄ and solvent evaporated. The resulting crude product was used inthe next step without further purification. LCMS calc. forC₂₉H₃₄F₃N₄O₂(M+H)⁺ m/z=527.3. found: 527.3.

Step 3. 4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-N-[(2′,6,6′-trifluorobiphenyl-3-yl)methyl]pyridin-3-amine

tert-Butyl[(3S,5R)-5-methyl-1-(3-{[(2′,6,6′-trifluorobiphenyl-3-yl)methyl]amino}pyridin-4-yl)piperidin-3-yl]carbamate(17 mg, 0.032 mmol) was dissolved in methanol (2 mL). Then 4.0 Msolution of HCl in dioxane (1 mL, 4 mmol) was added to the reactionmixture. The reaction mixture was stirred at room temperature overnight.Then the reaction mixture was neutralized by addition of the ammoniasolution and purified by RP-HPLC (water XBridge C18 column, 30 mm×100mm, 5 μm particle size, gradient elution with acetonitrile/watercontaining 0.1% NH₄OH, at flow rate of 60 mL/min). LCMS calc. forC₂₄H₂₆F₃N₄ (M+H)⁺ m/z=427.2. found: 427.2.

Example 261-(5′-((4-((3S,5R)-3-Amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-2,2′,6-trifluorobiphenyl-4-yl)cyclobutanol

This compound was synthesized using similar procedures as described inExample 25, using1-(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutanol(from Example 7, Step 2) to replace2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in Step2. LCMS calc. for C₂₈H₃₂F₃N₄O (M+H)⁺ m/z=497.3. found: 497.2. ¹H NMR(400 MHz, DMSO-d6) δ 7.78 (d, J=5.1 Hz, 1H), 7.75 (s, 1H), 7.57-7.49 (m,1H), 7.47 (d, J=6.9 Hz, 1H), 7.35 (d, J=9.6 Hz, 1H), 7.30 (d, J=9.6 Hz,2H), 6.81 (d, J=5.1 Hz, 1H), 5.82 (s, 1H), 5.36 (t, J=6.2 Hz, 1H), 4.44(d, J=5.9 Hz, 2H), 3.18 (dd, J=31.1, 8.1 Hz, 1H), 3.00-2.84 (m, 1H),2.43 (ddd, J=12.4, 8.9, 5.4 Hz, 3H), 2.34-2.24 (m, 3H), 2.10 (t, J=10.6Hz, 1H), 2.07-1.65 (m, 6H), 0.86 (d, J=6.4 Hz, 3H), 0.76 (q, J=12.0 Hz,1H) ppm.

Example 274-(5′-((4-((3S,5R)-3-Amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-2,2′,6-trifluorobiphenyl-4-yl)tetrahydro-2H-pyran-4-ol

This compound was synthesized using similar procedures as described inExample 25, using4-(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydro-2H-pyran-4-ol(Prepared by an analogous route to that described in Example 3) toreplace 2-(2,6-difluorophenyl)-4, 4,5,5-tetramethyl-1,3,2-dioxaborolanein Step 2. LCMS calc. for C₂₉H₃₄F₃N₄O₂(M+H)⁺ m/z=527.3. found: 527.3.

Example 28(3R,4R,5S)-3-Amino-1-[3-({[6-(2,6-difluorophenyl)pyridin-2-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-4-ol

Step 1. Methyl 6-(2,6-difluorophenyl)pyridine-2-carboxylate

Methyl 6-bromopyridine-2-carboxylate (from Aldrich, 300 mg, 1.39 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (110 mg, 0.14 mmol), potassium phosphate (880 mg, 4.2mmol) and magnet bar were placed in a vial with septum. The vial wasthen evacuated and backfilled with nitrogen three times. 1,4-Dioxane (10mL) and degassed water (2 mL) were added to the reaction mixture.Finally 2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(583 mg, 2.43 mmol) was added and the reaction mixture was stirred at65° C. for 1 h. Then the reaction mixture was diluted with EtOAc. Theresulting solution was washed with brine, dried over Na₂SO₄ and solventevaporated. The crude product was purified by Biotage Isolera to givethe desired compound (284 mg, 82%). LCMS calc. for C₁₃H₁₀F₂NO₂ (M+H)⁺m/z=250.1. found: 250.1.

Step 2. 6-(2,6-Difluorophenyl)pyridine-2-carboxylic acid

6-(2,6-Difluorophenyl)pyridine-2-carboxylate (284 mg, 1.14 mmol) wasdissolved in tetrahydrofuran (6 mL). Then methanol (4 mL) and 1.0Msolution of sodium hydroxide in water (2 mL, 2 mmol) were added andreaction mixture was stirred at room temperature for 30 min. After thistime pH was adjusted to 5 by addition of the 1M solution of HCl. Theproduct was then extracted with EtOAc and organic phase was washed withbrine and dried over Na₂SO₄. The solvents were evaporated under reducedpressure. Obtained solid product was used in the next step withoutfurther purification (260 mg, 96%). LCMS calc. for C₁₂H₈F₂NO₂ (M+H)⁺m/z=236.1. found 236.0.

Step 3. [6-(2,6-Difluorophenyl)pyridin-2-yl]methanol

To a solution of 6-(2,6-difluorophenyl)pyridine-2-carboxylic acid (260mg, 1.1 mmol) and triethylamine (162 μL, 1.16 mmol) in tetrahydrofuran(3 mL) was slowly added isobutyl chloroformate (0.15 mL, 1.16 mmol). Thereaction mixture was stirred at room temperature for 1 h. The formedprecipitate was filtered off and to obtained clear solution was slowlyadded the solution of sodium tetrahydroborate (84 mg, 2.2 mmol) in water(1 mL). Reaction mixture was stirred at room temperature for 30 min.Then water was added and the product was extracted with EtOAc. Combinedorganic fractions were washed with brine and dried over Na₂SO₄. Afterevaporation of the solvents under reduced pressure, obtained product wasused in the next step without further purification (116 mg, 48%). LCMScalc. for C₁₂H₁₀F₂NO (M+H)⁺ m/z=222.1. found 222.1.

Step 4. 6-(2,6-Difluorophenyl)pyridine-2-carbaldehyde

To a stirred solution of [6-(2,6-difluorophenyl)pyridin-2-yl]methanol(116 mg, 0.524 mmol) in DCM (4 mL) at 0° C. were added pyridine (51 μL,0.63 mmol) and Dess-Martin periodinane (234 mg, 0.551 mmol). Thereaction mixture was stirred at room temperature for 3 h. Then saturatedsolutions of NaHCO₃ in water (10 mL) and Na₂S₂O₃ in water (5 mL) wereadded and the reaction mixture was stirred for 30 min. Then the productwas extracted with DCM. Combined organic fractions were washed withbrine, dried over Na₂SO₄ and solvents were evaporated under reducedpressure. The crude product was purified by Biotage Isolera to give thedesired compound (95 mg, 83%). LCMS calc. for C₁₂H₈F₂NO (M+H)⁺m/z=220.1. found: 220.1.

Step 5. tert-Butyl{(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-[3-({[6-(2,6-difluorophenyl)pyridin-2-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-3-yl}carbamate

tert-Butyl((3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(Prepared in Intermediate 1, Step 11; 20.0 mg, 0.0458 mmol) and6-(2,6-difluorophenyl)pyridine-2-carbaldehyde (12 mg, 0.055 mmol) weredissolved in toluene (2.0 mL). Then catalytic amount of acetic acid wasadded and the reaction mixture was heated at 100° C. for 2 h. After thistime, the reaction mixture was cooled to room temperature and toluenewas evaporated under reduced pressure. The resulting intermediate iminewas dissolved in methanol (2.0 mL) and resulting solution was cooled to0° C. Then sodium tetrahydroborate (3.5 mg, 0.092 mmol) was slowly addedand the reaction mixture was stirred at room temperature for 30 min.After this time, water was added to the reaction mixture and product wasextracted with EtOAc. Combined organic fractions were washed with brine,dried over Na₂SO₄ and solvents were evaporated under reduced pressure.The resulting crude product was used in the next step without furtherpurification. LCMS calc. for C₃₄H₄₈F₂N₅O₃Si (M+H)⁺ m/z=640.4. found:640.3.

Step 6.(3R,4R,5S)-3-Amino-1-[3-({[6-(2,6-difluorophenyl)pyridin-2-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-4-ol

tert-Butyl{(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-[3-({[6-(2,6-difluorophenyl)pyridin-2-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-3-yl}carbamate(21 mg, 0.032 mmol) was dissolved in methanol (2 mL). Then 4.0 Msolution of HCl in dioxane (1 mL, 4 mmol) was added to the reactionmixture. The reaction mixture was stirred at room temperature overnight.Then the reaction mixture was neutralized by addition of the ammoniasolution and purified by RP-HPLC (water XBridge C18 column, 30 mm×100mm, 5 μm particle size, gradient elution with acetonitrile/watercontaining 0.1% NH₄OH, at flow rate of 60 mL/min). LCMS calc. forC₂₃H₂₆F₂N₅O (M+H)⁺ m/z=426.2. found: 426.2.

Example 294-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-N-{[6-(2,6-difluorophenyl)pyridin-2-yl]methyl}pyridin-3-amine

Step 1. tert-Butyl{(3S,5R)-1-[3-({[6-(2,6-difluorophenyl)pyridin-2-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-3-yl}carbamate

tert-Butyl[(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(Prepared in Intermediate 2, Step 6; 14.0 mg, 0.0458 mmol) and6-(2,6-difluorophenyl)pyridine-2-carbaldehyde (Prepared in Example 28,Step 4; 12 mg, 0.055 mmol) were dissolved in toluene (2 mL). Thencatalytic amount of acetic acid was added and the reaction mixture washeated at 100° C. for 2 h. After this time, the reaction mixture wascooled to room temperature and toluene was evaporated under reducedpressure. The resulting intermediate imine was dissolved in methanol (1mL) and resulting solution was cooled to 0° C. Then sodiumtetrahydroborate (3.5 mg, 0.092 mmol) was slowly added and the reactionmixture was stirred at room temperature for 30 min. After this time,water was added to the reaction mixture and product was extracted withEtOAc. Combined organic fractions were washed with brine, dried overNa₂SO₄ and solvents were evaporated under reduced pressure. Theresulting crude product was used in the next step without furtherpurification. LCMS calc. for C₂₈H₃₄F₂N₅O₂ (M+H)⁺ m/z=510.3. found:510.3.

Step 2.4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-N-{[6-(2,6-difluorophenyl)pyridin-2-yl]methyl}pyridin-3-amine

tert-Butyl{(3S,5R)-1-[3-({[6-(2,6-difluorophenyl)pyridin-2-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-3-yl}carbamate(16 mg, 0.032 mmol) was dissolved in methanol (2 mL). Then 4.0 Msolution of HCl in dioxane (1 mL, 4 mmol) was added to the reactionmixture. The reaction mixture was stirred at room temperature overnight.Then the reaction mixture was neutralized by addition of the ammoniasolution and purified by RP-HPLC (water XBridge C18 column, 30 mm×100mm, 5 μm particle size, gradient elution with acetonitrile/watercontaining 0.1% NH₄OH, at flow rate of 60 mL/min). LCMS calc. forC₂₃H₂₆F₂N₅ (M+H)⁺ m/z=410.2. found: 410.1.

Example 30(3R,4R,5S)-3-Amino-1-[3-({[2-(2,6-difluorophenyl)pyrimidin-4-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-4-ol

Step 1. (2-Chloropyrimidin-4-yl)methanol

To a solution of 2-chloropyrimidine-4-carboxylic acid (fromCombi-Blocks, 250 mg, 1.6 mmol) and triethylamine (231 μL, 1.66 mmol) intetrahydrofuran (5 mL) was slowly added isobutyl chloroformate (0.22 mL,1.66 mmol). Reaction mixture was stirred at room temperature for 1 h.The formed precipitate was filtered off and to obtained clear solutionwas slowly added solution of sodium tetrahydroborate (120 mg, 3.2 mmol)in water (1 mL). Reaction mixture was stirred at room temperature for 30min. Then water was added and the product was extracted with EtOAc.Combined organic fractions were washed with brine and dried with Na₂SO₄.After evaporation of the solvents under reduced pressure, obtainedproduct was used in the next step without further purification (223 mg,96%). LCMS calc. for C₅H₆ClN₂O (M+H)⁺ m/z=145.0. found 145.0.

Step 2. [2-(2,6-Difluorophenyl)pyrimidin-4-yl]methanol

(2-Chloropyrimidin-4-yl)methanol (223 mg, 1.54 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (120 mg, 0.15 mmol), potassium phosphate (980 mg, 4.6mmol) and magnet bar were placed in a vial with septum. The vial wasthen evacuated and backfilled with nitrogen three times. 1,4-Dioxane (12mL) and degassed water (2 mL) were added. Finally2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (590 mg,2.5 mmol) was added and the reaction mixture was stirred at 65° C. for 1h. Then the reaction mixture was diluted with EtOAc. The resultingsolution was washed with brine, dried over Na₂SO₄ and solventevaporated. The crude product was purified by Biotage Isolera to givethe desired compound (321 mg, 94%). LCMS calc. for C₁₁H₉F₂N₂O (M+H)⁺m/z=223.1. found: 223.1.

Step 3. 2-(2,6-Difluorophenyl)pyrimidine-4-carbaldehyde

To a stirred solution of [2-(2,6-difluorophenyl)pyrimidin-4-yl]methanol(321 mg, 1.44 mmol) in DCM (10 mL) at 0° C. were added pyridine (140 μL,1.7 mmol) and Dess-Martin periodinane (643 mg, 1.52 mmol). The reactionmixture was stirred at room temperature for 3 h. Then saturatedsolutions of NaHCO₃ in water (10 mL) and Na₂S₂O₃ in water (5 mL) wereadded and the reaction mixture was stirred for 30 min. Then product wasextracted with DCM. Combined organic fractions were washed with brine,dried over Na₂SO₄ and solvents were evaporated under reduced pressure.The crude product was purified by Biotage Isolera to give the desiredcompound (244 mg, 77%). LCMS calc. for C₁₁H₇F₂N₂O (M+H)⁺ m/z=221.1.found: 221.0.

Step 4. tert-Butyl{(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-[3-({[2-(2,6-difluorophenyl)pyrimidin-4-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-3-yl}carbamate

tert-Butyl((3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(Prepared in Intermediate 1, Step 11; 20.0 mg, 0.0458 mmol) and2-(2,6-difluorophenyl)pyrimidine-4-carbaldehyde (12 mg, 0.055 mmol) weredissolved in toluene (2.0 mL). Then catalytic amount of acetic acid wasadded and the reaction mixture was heated at 100° C. for 2 h. After thistime, the reaction mixture was cooled to room temperature and toluenewas evaporated under reduced pressure. The resulting intermediate iminewas dissolved in methanol (2.0 mL) and resulting solution was cooled to0° C. Then sodium tetrahydroborate (3.5 mg, 0.092 mmol) was slowly addedand the reaction mixture was stirred at room temperature for 30 min.After this time, water was added to the reaction mixture and product wasextracted with EtOAc. Combined organic fractions were washed with brine,dried over Na₂SO₄ and solvents were evaporated under reduced pressure.The resulting crude product was used in the next step without furtherpurification. LCMS calc. for C₃₃H₄₇F₂N₆O₃Si (M+H)⁺ m/z=641.3. found:641.4.

Step 5.(3R,4R,5S)-3-Amino-1-[3-({[2-(2,6-difluorophenyl)pyrimidin-4-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-4-ol

tert-Butyl{(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-[3-({[2-(2,6-difluorophenyl)pyrimidin-4-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-3-yl}carbamate(21 mg, 0.032 mmol) was dissolved in methanol (2 mL). Then 4.0 Msolution of HCl in dioxane (1 mL, 4 mmol) was added to the reactionmixture. The reaction mixture was stirred at room temperature overnight.Then the reaction mixture was neutralized by addition of the ammoniasolution and purified by RP-HPLC (water XBridge C18 column, 30 mm×100mm, 5 μm particle size, gradient elution with acetonitrile/watercontaining 0.1% NH₄OH, at flow rate of 60 mL/min). LCMS calc. forC₂₂H₂₅F₂N₆O (M+H)⁺ m/z=427.2. found: 427.2.

Example 314-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-N-{[2-(2,6-difluorophenyl)pyrimidin-4-yl]methyl}pyridin-3-amine

Step 1. tert-Butyl{(3S,5R)-1-[3-({[2-(2,6-difluorophenyl)pyrimidin-4-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-3-yl}carbamate

tert-Butyl[(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(Prepared in Intermediate 2, Step 6; 14.0 mg, 0.0458 mmol) and2-(2,6-difluorophenyl)pyrimidine-4-carbaldehyde (Prepared in Example 30,Step 3; 12 mg, 0.055 mmol) were dissolved in toluene (2 mL). Thencatalytic amount of acetic acid was added and the reaction was heated at100° C. for 2 h. After this time, the reaction mixture was cooled toroom temperature and toluene was evaporated under reduced pressure. Theresulting intermediate imine was dissolved in methanol (1 mL) andresulting solution was cooled to 0° C. Then sodium tetrahydroborate (3.5mg, 0.092 mmol) was slowly added and the reaction mixture was stirred atroom temperature for 30 min. After this time, water was added to thereaction mixture and product was extracted with EtOAc. Combined organicfractions were washed with brine, dried over Na₂SO₄ and solvents wereevaporated under reduced pressure. The resulting crude product was usedin the next step without further purification. LCMS calc. forC₂₇H₃₃F₂N₆O₂(M+H)⁺ m/z=511.3. found: 511.2.

Step 2.4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-N-{[2-(2,6-difluorophenyl)pyrimidin-4-yl]methyl}pyridin-3-amine

tert-Butyl{(3S,5R)-1-[3-({[2-(2,6-difluorophenyl)pyrimidin-4-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-3-yl}carbamate(16 mg, 0.032 mmol) was dissolved in methanol (2 mL). Then 4.0 Msolution of HCl in dioxane (1 mL, 4 mmol) was added to the reactionmixture. The reaction mixture was stirred at room temperature overnight.Then the reaction mixture was neutralized by addition of the ammoniasolution and purified by RP-HPLC (water XBridge C18 column, 30 mm×100mm, 5 μm particle size, gradient elution with acetonitrile/watercontaining 0.1% NH₄OH, at flow rate of 60 mL/min). LCMS calc. forC₂₂H₂₅F₂N₆ (M+H)⁺ m/z=411.2. found: 411.2.

Example 32(3R,4R,5S)-3-Amino-1-(3-(((6-(2,6-difluoro-4-morpholinophenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol

Step 1. 4-(3,5-Difluorophenyl)morpholine

1-Bromo-3,5-difluorobenzene (Sigma-Aldrich, 600 μL, 5.2 mmol), cesiumcarbonate (4.2 g, 13 mmol) andchloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(210 mg, 0.26 mmol) were placed in a vial. The vial was then evacuatedand backfilled with nitrogen three times. After this 1,4-dioxane (8 mL)and morpholine (900 μL, 10 mmol) were added to the reaction mixture. Thereaction mixture was stirred at 110° C. overnight. After this time thereaction was quenched by the addition of water and the product wasextracted with EtOAc. Combined organic fractions were washed with brine,dried over Na₂SO₄ and the solvents were evaporated under reducedpressure. The crude product was purified by Biotage Isolera to give thedesired compound (450 mg, 45%). LCMS calc. for C₁₀H₁₂F₂NO (M+H)⁺m/z=200.1. found: 200.0.

Step 2.4-[3,5-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]morpholine

4-(3,5-Difluorophenyl)morpholine (250 mg, 1.26 mmol) and a magnet barwere placed in a vial. The vial was evacuated and backfilled withnitrogen three times. After addition of tetrahydrofuran (6.0 mL), thereaction mixture was cooled to −78° C. Then 1.6M solution ofn-butyllithium in hexanes (780 μL, 1.2 mmol) was slowly added and thereaction mixture was stirred at −78° C. for 1 h. After this time2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (510 μL, 2.5 mmol)was slowly added to the reaction mixture. After stirring at −78° C. for5 min, the reaction mixture was allowed to warm to room temperature andwas stirred at room temperature for 1 h. After this time the reactionwas carefully quenched by the addition of saturated solution of ammoniumchloride. The product was extracted with EtOAc. Combined organicfractions were washed with brine, dried over Na₂SO₄ and solvents wereevaporated under reduced pressure. The resulting product was used in thenext step without further purification (305 mg, 75%). LCMS calc. forC₁₆H₂₃BF₂NO₃ (M+H)⁺ m/z=326.2. found: 326.1.

Step 3. tert-Butyl((3R,4R,5S)-4-((tert-butyldimethylsilyl)oxy)-1-(3-(((6-(2,6-difluoro-4-morpholinophenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-3-yl)carbamate

tert-Butyl((3R,4R,5S)-1-(3-{[(6-bromo-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(Intermediate 1, 20.0 mg, 0.0320 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (2.5 mg, 0.0032 mmol), potassium phosphate (20 mg, 0.096mmol) and magnet bar were placed in a vial with septum. The vial wasthen evacuated and backfilled with nitrogen three times. 1,4-Dioxane(2.5 mL) and degassed water (0.3 mL) were added to the reaction mixtureto the reaction mixture. Finally4-[3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]morpholine(Prepared in Example 32, Step 2; 17 mg, 0.051 mmol) was added and thereaction mixture was stirred at 65° C. for 1 h. Then the reactionmixture was diluted with EtOAc. The resulting solution was washed withbrine, dried over Na₂SO₄ and solvent evaporated. The resulting crudeproduct was used in the next step without further purification. LCMScalc. for C₃₈H₅₄F₃N₆O₄Si (M+H)⁺ m/z=743.4. found: 743.4.

Step 4.(3R,4R,5S)-3-Amino-1-(3-(((6-(2,6-difluoro-4-morpholinophenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol

tert-Butyl((3R,4R,5S)-4-((tert-butyldimethylsilyl)oxy)-1-(3-(((6-(2,6-difluoro-4-morpholinophenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-3-yl)carbamate(24 mg, 0.032 mmol) was dissolved in methanol (2 mL). Then 4.0 Msolution of HCl in dioxane (1 mL, 4 mmol) was added to the reactionmixture. The reaction mixture was stirred at room temperature overnight.Then the reaction mixture was neutralized by addition of the ammoniasolution and purified by RP-HPLC (water XBridge C18 column, 30 mm×100mm, 5 μm particle size, gradient elution with acetonitrile/watercontaining 0.1% NH₄OH, at flow rate of 60 mL/min). LCMS calc. forC₂₇H₃₂F₃N₆O₂(M+H)⁺ m/z=529.3. found: 529.3.

Example 334-((3S,5R)-3-Amino-5-methylpiperidin-1-yl)-N-((6-(2,6-difluoro-4-morpholinophenyl)-5-fluoropyridin-2-yl)methyl)pyridin-3-amine

Step 1. tert-butyl((3S,5R)-1-(3-(((6-(2,6-difluoro-4-morpholinophenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-3-yl)carbamate

tert-Butyl[(3S,5R)-1-(3-{[(6-bromo-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(intermediate 2, 15.8 mg, 0.0320 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (2.5 mg, 0.0032 mmol), potassium phosphate (20 mg, 0.096mmol) and magnet bar were placed in a vial with septum. The vial wasthen evacuated and backfilled with nitrogen three times. 1,4-Dioxane(2.5 mL) and degassed water (0.3 mL) were added to the reaction mixtureto the reaction mixture. Finally4-[3,5-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]morpholine(Prepared in Example 32, Step 2; 17 mg, 0.051 mmol) was added and thereaction mixture was stirred at 65° C. for 1 h. Then the reactionmixture was diluted with EtOAc. The resulting solution was washed withbrine, dried over Na₂SO₄ and solvent evaporated. The resulting crudeproduct was used in the next step without further purification. LCMScalc. for C₃₂H₄₀F₃N₆O₃(M+H)⁺ m/z=613.3. found: 613.3.

Step 2.4-((3S,5R)-3-Amino-5-methylpiperidin-1-yl)-N-((6-(2,6-difluoro-4-morpholinophenyl)-5-fluoropyridin-2-yl)methyl)pyridin-3-amine

tert-Butyl(3S,5R)-1-(3-((6-(2,6-difluoro-4-morpholinophenyl)-5-fluoropyridin-2-yl)methylamino)pyridin-4-yl)-5-methylpiperidin-3-ylcarbamate(20 mg, 0.032 mmol) was dissolved in methanol (2 mL). Then 4.0 Msolution of HCl in dioxane (1 mL, 4 mmol) was added to the reactionmixture to the reaction mixture. The reaction mixture was stirred atroom temperature overnight. Then the reaction mixture was neutralized byaddition of the ammonia solution and purified by RP-HPLC (water XBridgeC18 column, 30 mm×100 mm, 5 μm particle size, gradient elution withacetonitrile/water containing 0.1% NH₄OH, at flow rate of 60 mL/min).LCMS calc. for C₂₇H₃₂F₃N₆O (M+H)⁺ m/z=513.3. found: 513.2. ¹H NMR (400MHz, DMSO-d6) δ 7.88-7.81 (m, 2H), 7.79 (s, 1H), 7.52 (dd, J=8.6, 3.8Hz, 1H), 6.87-6.77 (m, 3H), 5.73 (t, J=5.4 Hz, 1H), 4.58-4.40 (m, 3H),3.81-3.71 (m, 4H), 3.30-3.26 (m, 4H), 3.26-3.11 (m, 2H), 2.91 (d, J=10.8Hz, 1H), 2.20 (t, J=10.6 Hz, 1H), 2.00 (t, J=11.1 Hz, 1H), 1.86 (d,J=12.1 Hz, 1H), 1.77 (d, J=10.8 Hz, 1H), 0.87-0.74 (m, 4H) ppm.

Example 344-((3S,5R)-3-Amino-5-(trifluoromethyl)piperidin-1-yl)-N-((6-(2,6-difluoro-4-morpholinophenyl)-5-fluoropyridin-2-yl)methyl)pyridin-3-amine

Step 1. tert-butyl((3S,5R)-1-(3-(((6-(2,6-difluoro-4-morpholinophenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl)carbamate

tert-Butyl((3S,5R)-1-(3-(((6-bromo-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl)carbamate(intermediate 3, 17.5 mg, 0.0320 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (2.5 mg, 0.0032 mmol), potassium phosphate (20 mg, 0.096mmol) and magnet bar were placed in a vial with septum. The vial wasthen evacuated and backfilled with nitrogen three times. 1,4-Dioxane(2.5 mL) and degassed water (0.3 mL) were added to the reaction mixtureto the reaction mixture. Finally,4-[3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]morpholine(Prepared in Example 32, Step 2; 17 mg, 0.051 mmol) was added and thereaction mixture was stirred at 65° C. for 1 h. Then the reactionmixture was diluted with EtOAc. The resulting solution was washed withbrine, dried over Na₂SO₄ and solvent evaporated. The resulting crudeproduct was used in the next step without further purification. LCMScalc. for C₃₂H₃₇F₆N₆O₃(M+H)⁺ m/z=667.3. found: 667.3.

Step 2.4-((3S,5R)-3-amino-5-(trifluoromethyl)piperidin-1-yl)-N-((6-(2,6-difluoro-4-morpholinophenyl)-5-fluoropyridin-2-yl)methyl)pyridin-3-amine

tert-Butyl(3S,5R)-1-(3-((6-(2,6-difluoro-4-morpholinophenyl)-5-fluoropyridin-2-yl)methylamino)pyridin-4-yl)-5-(trifluoromethyl)piperidin-3-ylcarbamate(21 mg, 0.032 mmol) was dissolved in methanol (2 mL). Then 4.0 Msolution of HCl in dioxane (1 mL, 4 mmol) was added to the reactionmixture. The reaction mixture was stirred at room temperature overnight.Then the reaction mixture was neutralized by addition of the ammoniasolution and purified by RP-HPLC (water XBridge C18 column, 30 mm×100mm, 5 μm particle size, gradient elution with acetonitrile/watercontaining 0.1% NH₄OH, at flow rate of 60 mL/min). LCMS calc. forC₂₇H₂₉F₆N₆O (M+H)⁺ m/z=567.2. found: 567.2. ¹H NMR (400 MHz, DMSO-d6) δ7.89-7.80 (m, 3H), 7.50 (dd, J=8.6, 3.8 Hz, 1H), 6.91 (d, J=5.1 Hz, 1H),6.80 (d, J=11.8 Hz, 1H), 5.86 (t, J=5.5 Hz, 1H), 4.60-4.44 (m, 2H),3.80-3.69 (m, 4H), 3.45-3.35 (m, 1H), 3.30-3.26 (m, 4H), 3.24-3.15 (m,2H), 2.97-2.83 (m, 1H), 2.80-2.66 (m, 1H), 2.43-2.26 (m, 2H), 2.01 (d,J=12.0 Hz, 1H), 1.70 (br, 1H), 1.16 (q, J=12.3 Hz, 1H) ppm.

Example 35(3R,4R,5S)-3-Amino-1-{3-[({6-[2,6-difluoro-4-(hydroxymethyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol

Step 1.[3,5-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol

To a solution of3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(Sigma-Aldrich, 500.0 mg, 1.865 mmol) in methanol (10 mL) was slowlyadded sodium tetrahydroborate (150 mg, 3.9 mmol) at 0° C. Reactionmixture was stirred at room temperature for 1 h. Then the reactionmixture was diluted with EtOAc. The resulting solution was washed withbrine, dried over Na₂SO₄ and solvents were evaporated under reducedpressure. The resulting crude product was used in the next step withoutfurther purification.

Step 2. tert-Butyl((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-{3-[({6-[2,6-difluoro-4-(hydroxymethyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate

tert-Butyl((3R,4R,5S)-1-(3-{[(6-bromo-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(intermediate 1, 20.0 mg, 0.0320 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (2.5 mg, 0.0032 mmol), potassium phosphate (20 mg, 0.096mmol) and magnet bar were placed in a vial with septum. The vial wasthen evacuated and backfilled with nitrogen three times. 1,4-Dioxane(2.5 mL) and degassed water (0.3 mL) were added to the reaction mixture.Finally[3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol(14 mg, 0.051 mmol) was added and the reaction mixture was stirred at65° C. for 1 h. Then the reaction mixture was diluted with EtOAc. Theresulting solution was washed with brine, dried over Na₂SO₄ and solventevaporated. The resulting crude product was used in the next stepwithout further purification. LCMS calc. for C₃₅H₄₉F₃N₅O₄Si (M+H)⁺m/z=688.4. found: 688.4.

Step 3.(3R,4R,5S)-3-Amino-1-{3-[({6-[2,6-difluoro-4-(hydroxymethyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol

tert-Butyl((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-{3-[({6-[2,6-difluoro-4-(hydroxymethyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate(22 mg, 0.032 mmol) was dissolved in methanol (2 mL). Then 4.0 Msolution of HCl in dioxane (1 mL, 4 mmol) was added to the reactionmixture. The reaction mixture was stirred at room temperature overnight.Then the reaction mixture was neutralized by addition of the ammoniasolution and purified by RP-HPLC (water XBridge C18 column, 30 mm×100mm, 5 μm particle size, gradient elution with acetonitrile/watercontaining 0.1% NH₄OH, at flow rate of 60 mL/min). LCMS calc. forC₂₄H₂₇F₃N₅O₂ (M+H)⁺ m/z=474.2. found: 474.2. ¹H NMR (400 MHz, DMSO-d6) δ7.90 (t, J=9.0 Hz, 1H), 7.80 (d, J=5.1 Hz, 1H), 7.75 (s, 1H), 7.56 (dd,J=8.7, 3.9 Hz, 1H), 7.20 (d, J=8.6 Hz, 2H), 6.83 (d, J=5.1 Hz, 1H), 5.61(t, J=5.8 Hz, 1H), 5.53 (br, 1H), 4.75 (d, J=4.5 Hz, 1H), 4.61 (d, J=4.3Hz, 2H), 4.57-4.50 (m, 2H), 3.26-3.15 (m, 2H), 2.77-2.63 (m, 2H), 2.33(t, J=10.6 Hz, 1H), 2.23 (t, J=11.5 Hz, 1H), 1.80-1.65 (m, 1H), 1.57(br, 1H), 0.88 (d, J=6.6 Hz, 3H) ppm.

Example 36(4-{6-[({4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]pyridin-3-yl)}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)methanol

Step 1. tert-Butyl((3S,5R)-1-{3-[({6-[2,6-difluoro-4-(hydroxymethyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate

tert-Butyl[(3S,5R)-1-(3-{[(6-bromo-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(intermediate 2, 15.8 mg, 0.0320 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (2.5 mg, 0.0032 mmol), potassium phosphate (20 mg, 0.096mmol) and magnet bar were placed in a vial with septum. The vial wasthen evacuated and backfilled with nitrogen three times. 1,4-Dioxane(2.5 mL) and degassed water (0.3 mL) were added to the reaction mixture.Finally[3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol(14 mg, 0.051 mmol) was added and the reaction mixture was stirred at65° C. for 1 h. Then the reaction mixture was diluted with EtOAc. Theresulting solution was washed with brine, dried over Na₂SO₄ and solventevaporated. The resulting crude product was used in the next stepwithout further purification. LCMS calc. for C₂₉H₃₅F₃N₅O₃(M+H)⁺m/z=558.3. found: 558.2.

Step 2.(4-{6-[({4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)methanol

tert-Butyl((3S,5R)-1-{3-[({6-[2,6-difluoro-4-(hydroxymethyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate(18 mg, 0.032 mmol) was dissolved in methanol (2 mL). Then 4.0 Msolution of HCl in dioxane (1 mL, 4 mmol) was added to the reactionmixture. The reaction mixture was stirred at room temperature overnight.Then the reaction mixture was neutralized by addition of the ammoniasolution and purified by RP-HPLC (water XBridge C18 column, 30 mm×100mm, 5 μm particle size, gradient elution with acetonitrile/watercontaining 0.1% NH₄OH, at flow rate of 60 mL/min). LCMS calc. forC₂₄H₂₇F₃N₅O (M+H)⁺ m/z=458.2. found: 458.2. ¹H NMR (400 MHz, DMSO-d6) δ7.92 (t, J=9.0 Hz, 1H), 7.82 (d, J=5.0 Hz, 1H), 7.79 (s, 1H), 7.59 (dd,J=8.7, 3.9 Hz, 1H), 7.22 (d, J=8.7 Hz, 2H), 6.82 (d, J=5.1 Hz, 1H), 5.70(t, J=5.5 Hz, 1H), 4.62 (s, 2H), 4.52 (qd, J=16.4, 5.4 Hz, 3H),3.20-3.10 (m, 2H), 2.77 (dq, J=10.5, 5.4, 3.9 Hz, 2H), 2.13 (t, J=10.5Hz, 1H), 1.97 (t, J=11.1 Hz, 1H), 1.86-1.71 (m, 1H), 1.61 (s, 1H), 0.77(d, J=6.5 Hz, 3H), 0.74-0.67 (m, 1H) ppm.

Example 37(3R,4R,5S)-3-Amino-1-[3-({[6-(5,7-difluoroquinolin-6-yl)-5-fluoropyridin-2-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-4-ol

Step 1. 5,7-Difluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline

6-Bromo-5,7-difluoroquinoline (Sigma-Aldrich, 500.0 mg, 2.049 mmol),4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl](fromAldrich, 780 mg, 3.07 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith DCM (1:1) (170 mg, 0.20 mmol), potassium acetate (600 mg, 6.1 mmol)and magnet bar were placed in a vial with septum. The vial was thenevacuated and backfilled with nitrogen three times. 1,4-Dioxane (9 mL)was added and the reaction mixture was stirred at 100° C. overnight.Then the reaction mixture was diluted with EtOAc. The resulting solutionwas washed with brine, dried over Na₂SO₄ and solvents were evaporatedunder reduced pressure. The resulting crude product was used in the nextstep without further purification. LCMS calc. for C₉H₇BF₂NO₂ (pinacolester hydrolyzed to acid on HPLC, M-C₆H₁₂+H)⁺ m/z=210.1. found: 210.1.

Step 2. tert-Butyl{(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-[3-({[6-(5,7-difluoroquinolin-6-yl)-5-fluoropyridin-2-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-3-yl}carbamate

tert-Butyl((3R,4R,5S)-1-(3-{[(6-bromo-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(intermediate 1, 20.0 mg, 0.0320 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (2.5 mg, 0.0032 mmol), potassium phosphate (20 mg, 0.096mmol) and magnet bar were placed in a vial with septum. The vial wasthen evacuated and backfilled with nitrogen three times. 1,4-Dioxane(2.5 mL) and degassed water (0.3 mL) were added to the reaction mixture.Finally5,7-difluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline(15 mg, 0.051 mmol) was added and the reaction mixture was stirred at65° C. for 1 h. Then the reaction mixture was diluted with EtOAc. Theresulting solution was washed with brine, dried over Na₂SO₄ and solventevaporated. The resulting crude product was used in the next stepwithout further purification. LCMS calc. for C₃₇H₄₈F₃N₆O₃Si (M+H)⁺m/z=709.4. found: 709.4.

Step 3. (3R,4R,5S)-3-Amino-1-[3-({[6-(5,7-difluoroquinolin-6-yl)-5-fluoropyridin-2-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-4-ol

tert-Butyl{(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-[3-({[6-(5,7-difluoroquinolin-6-yl)-5-fluoropyridin-2-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-3-yl}carbamate(23 mg, 0.032 mmol) was dissolved in methanol (2 mL). Then 4.0 Msolution of HCl in dioxane (1 mL, 4 mmol) was added to the reactionmixture. The reaction mixture was stirred at room temperature overnight.Then the reaction mixture was neutralized by addition of the ammoniasolution and purified by RP-HPLC (water XBridge C18 column, 30 mm×100mm, 5 μm particle size, gradient elution with acetonitrile/watercontaining 0.1% NH₄OH, at flow rate of 60 mL/min). LCMS calc. forC₂₆H₂₆F₃N₆O (M+H)⁺ m/z=495.2. found: 495.2.

Example 384-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-N-{[6-(5,7-difluoroquinolin-6-yl)-5-fluoropyridin-2-yl]methyl}pyridin-3-amine

Step 1. tert-Butyl {(3S,5R)-1-[3-({[6-(5,7-difluoroquinolin-6-yl)-5-fluoropyridin-2-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-3-yl}carbamate

tert-Butyl[(3S,5R)-1-(3-{[(6-bromo-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(intermediate 2, 15.8 mg, 0.0320 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (2.5 mg, 0.0032 mmol), potassium phosphate (20 mg, 0.096mmol) and magnet bar were placed in a vial with septum. The vial wasthen evacuated and backfilled with nitrogen three times. 1,4-Dioxane(2.5 mL) and degassed water (0.3 mL) were added to the reaction mixture.Finally5,7-difluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline(15 mg, 0.051 mmol) was added and the reaction mixture was stirred at65° C. for 1 h. Then the reaction mixture was diluted with EtOAc. Theresulting solution was washed with brine, dried over Na₂SO₄ and solventevaporated. The resulting crude product was used in the next stepwithout further purification. LCMS calc. for C₃₁H₃₄F₃N₆O₂(M+H)⁺m/z=579.3. found: 579.2.

Step 2. 4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-N-{[6-(5,7-difluoroquinolin-6-yl)-5-fluoropyridin-2-yl]methyl}pyridin-3-amine

tert-Butyl{(3S,5R)-1-[3-({[6-(5,7-difluoroquinolin-6-yl)-5-fluoropyridin-2-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-3-yl}carbamate(18 mg, 0.032 mmol) was dissolved in methanol (2 mL). Then 4.0 Msolution of HCl in dioxane (1 mL, 4 mmol) was added to the reactionmixture. The reaction mixture was stirred at room temperature overnight.Then the reaction mixture was neutralized by addition of the ammoniasolution and purified by RP-HPLC (water XBridge C18 column, 30 mm×100mm, 5 μm particle size, gradient elution with acetonitrile/watercontaining 0.1% NH₄OH, at flow rate of 60 mL/min). LCMS calc. forC₂₆H₂₆F₃N₆ (M+H)⁺ m/z=479.2. found: 479.1.

Example 39(3R,4R,5S)-3-Amino-1-{3-[({6-[2,6-difluoro-4-(morpholin-4-ylmethyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol

Step 1.4-[3,5-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]morpholine

To a solution of3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(Sigma-Aldrich, 220 mg, 0.81 mmol) in DCM (3 mL) was added morpholine(92.0 μL, 1.05 mmol), followed by the addition of acetic acid (117 μL,2.06 mmol). The resulting reaction mixture was stirred at roomtemperature for 1 h. Then sodium triacetoxyborohydride (598 mg, 2.82mmol) was added in one portion. The resulting reaction mixture wasstirred at room temperature for 2 h. After this time, the reactionmixture was diluted with DCM and washed with saturated aq. NaHCO₃ andbrine. The organic layer was dried over Na₂SO₄, filtered andconcentrated under reduced pressure to afford the crude desired productwhich was directly used in the next step without further purification(160 mg, 59%). LCMS calc. for C₁₁H₁₅BF₂NO₃ (pinacol ester hydrolyzed toboronic acid on HPLC, M-C₆H₁₂+H)⁺ m/z=258.1. found: 258.1.

Step 2. tert-Butyl((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-{3-[({6-[2,6-difluoro-4-(morpholin-4-ylmethyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate

tert-Butyl((3R,4R,5S)-1-(3-{[(6-bromo-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(intermediate 1, 20.0 mg, 0.0320 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (2.5 mg, 0.0032 mmol), potassium phosphate (20 mg, 0.096mmol) and magnet bar were placed in a vial with septum. The vial wasthen evacuated and backfilled with nitrogen three times. 1,4-Dioxane(2.5 mL) and degassed water (0.3 mL) were added to the reaction mixture.Finally4-[3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]morpholine(17 mg, 0.051 mmol) was added and the reaction mixture was stirred at65° C. for 1 h. Then the reaction mixture was diluted with EtOAc. Theresulting solution was washed with brine, dried over Na₂SO₄ and solventevaporated. The resulting crude product was used in the next stepwithout further purification. LCMS calc. for C₃₉H₅₆F₃N₆O₄Si (M+H)⁺m/z=757.4. found: 757.3.

Step 3.(3R,4R,5S)-3-Amino-1-{3-[({6-[2,6-difluoro-4-(morpholin-4-ylmethyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol

tert-Butyl((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-{3-[({6-[2,6-difluoro-4-(morpholin-4-ylmethyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate(24 mg, 0.032 mmol) was dissolved in methanol (2 mL). Then 4.0 Msolution of HCl in dioxane (1 mL, 4 mmol) was added to the reactionmixture. The reaction mixture was stirred at room temperature overnight.Then the reaction mixture was neutralized by addition of the ammoniasolution and purified by RP-HPLC (water XBridge C18 column, 30 mm×100mm, 5 μm particle size, gradient elution with acetonitrile/watercontaining 0.1% NH₄OH, at flow rate of 60 mL/min). LCMS calc. forC₂₈H₃₄F₃N₆O₂(M+H)⁺ m/z=543.3. found: 543.2. ¹H NMR (400 MHz, DMSO-d6) δ7.91 (t, J=9.0 Hz, 1H), 7.81 (d, J=5.1 Hz, 1H), 7.76 (s, 1H), 7.57 (dd,J=8.7, 3.9 Hz, 1H), 7.23 (d, J=8.6 Hz, 2H), 6.83 (d, J=5.1 Hz, 1H), 5.62(t, J=5.7 Hz, 1H), 4.74 (d, J=4.3 Hz, 1H), 4.60-4.43 (m, 2H), 3.68-3.59(m, 4H), 3.58 (s, 2H), 3.24-3.13 (m, 2H), 2.75-2.64 (m, 2H), 2.49-2.40(m, 4H), 2.34 (t, J=10.5 Hz, 1H), 2.21 (t, J=11.6 Hz, 1H), 1.68 (s, 1H),1.61 (s, 1H), 0.86 (d, J=6.6 Hz, 3H) ppm.

Example 40(3R,4R,5S)-3-Amino-1-(3-(((6-(2,6-difluoro-4-((methylamino)methyl)phenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol

This compound was synthesized according to the procedures described inExample 39, using 2.0 M solution of methanamine in THF to replacemorpholine in Step 1. LCMS calc. for C₂₅H₃₀F₃N₆O (M+H)⁺ m/z=487.2.found: 487.2.

Example 41(3R,4R,5S)-3-Amino-1-(3-(((6-(4-(azetidin-1-ylmethyl)-2,6-difluorophenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol

This compound was synthesized using similar procedures as described inExample 39, using azetidine to replace morpholine in Step 1. LCMS calc.for C₂₇H₃₂F₃N₆O (M+H)⁺ m/z=513.3. found: 513.3. ¹H NMR (400 MHz,DMSO-d6) δ 7.90 (t, J=9.0 Hz, 1H), 7.80 (d, J=5.1 Hz, 1H), 7.75 (s, 1H),7.56 (dd, J=8.7, 3.9 Hz, 1H), 7.16 (d, J=8.6 Hz, 2H), 6.83 (d, J=5.1 Hz,1H), 5.61 (t, J=5.7 Hz, 1H), 4.74 (s, 1H), 4.58-4.46 (m, 3H), 3.63 (s,2H), 3.21 (t, J=7.0 Hz, 6H), 2.76-2.63 (m, 2H), 2.33 (t, J=10.5 Hz, 1H),2.22 (t, J=11.5 Hz, 1H), 2.03 (p, J=7.0 Hz, 2H), 1.69 (s, 1H), 1.60 (s,1H), 0.86 (d, J=6.5 Hz, 3H) ppm.

Example 42(3R,4R,5S)-3-Amino-1-(3-(((6-(2,6-difluoro-4-(((R)-3-hydroxypyrrolidin-1-yl)methyl)phenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol

This compound was synthesized according to the procedures described inExample 39, using (R)-pyrrolidin-3-ol (from Aldrich) to replacemorpholine in Step 1. LCMS calc. for C₂₈H₃₄F₃N₆O₂(M+H)⁺ m/z=543.3.found: 543.3. ¹H NMR (400 MHz, DMSO-d6) δ 7.90 (t, J=9.0 Hz, 1H), 7.80(d, J=5.1 Hz, 1H), 7.75 (s, 1H), 7.57 (dd, J=8.7, 3.9 Hz, 1H), 7.22 (d,J=8.6 Hz, 2H), 6.83 (d, J=5.1 Hz, 1H), 5.62 (t, J=5.8 Hz, 1H), 4.74 (s,1H), 4.57-4.47 (m, 2H), 4.23 (s, 1H), 3.68 (q, J=14.1 Hz, 2H), 3.27-3.15(m, 2H), 2.78-2.62 (m, 5H), 2.50-2.44 (m, 1H), 2.40 (dd, J=9.6, 3.6 Hz,1H), 2.34 (t, J=10.6 Hz, 1H), 2.22 (t, J=11.5 Hz, 1H), 2.04 (dq, J=14.2,7.6 Hz, 1H), 1.70 (s, 1H), 1.65-1.55 (m, 1H), 0.87 (d, J=6.5 Hz, 3H)ppm.

Example 43(3R,4R,5S)-3-Amino-1-(3-(((6-(2,6-difluoro-4-(((S)-3-hydroxypyrrolidin-1-yl)methyl)phenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol

This compound was synthesized according to the procedures described inExample 39, using (S)-pyrrolidin-3-ol (from Aldrich) to replacemorpholine in Step 1. LCMS calc. for C₂₈H₃₄F₃N₆O₂(M+H)⁺ m/z=543.3.found: 543.3. ¹H NMR (400 MHz, DMSO-d6) δ 7.90 (t, J=9.0 Hz, 1H), 7.80(d, J=5.1 Hz, 1H), 7.76 (s, 1H), 7.57 (dd, J=8.7, 3.9 Hz, 1H), 7.22 (d,J=8.6 Hz, 2H), 6.83 (d, J=5.1 Hz, 1H), 5.62 (t, J=5.8 Hz, 1H), 4.74 (d,J=4.4 Hz, 1H), 4.58-4.49 (m, 2H), 4.23 (s, 1H), 3.76-3.59 (m, 2H),3.25-3.12 (m, 1H), 2.76-2.61 (m, 5H), 2.49-2.43 (m, 2H), 2.40 (dd,J=9.7, 3.5 Hz, 1H), 2.34 (t, J=10.6 Hz, 1H), 2.22 (t, J=11.5 Hz, 1H),2.10-1.98 (m, 2H), 1.70 (s, 1H), 1.65-1.55 (m, 1H), 0.87 (d, J=6.5 Hz,3H) ppm.

Example 44(R)-1-(4-(6-((4-((3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-3,5-difluorobenzyl)pyrrolidine-3-carbonitrile

This compound was synthesized according to the procedures described inExample 39, using (R)-pyrrolidine-3-carbonitrile (from Tyger) to replacemorpholine in Step 1. LCMS calc. for C₂₉H₃₃F₃N₇O (M+H)⁺ m/z=552.3.found: 552.3. ¹H NMR (400 MHz, DMSO-d6) δ 7.91 (t, J=9.0 Hz, 1H), 7.81(d, J=5.1 Hz, 1H), 7.76 (s, 1H), 7.57 (dd, J=8.6, 3.9 Hz, 1H), 7.23 (d,J=8.5 Hz, 2H), 6.83 (d, J=5.1 Hz, 1H), 5.63 (t, J=5.6 Hz, 1H), 4.77 (s,1H), 4.61-4.46 (m, 2H), 3.74 (s, 2H), 3.26-3.12 (m, 2H), 2.88-2.64 (m,5H), 2.62-2.53 (m, 1H), 2.39-2.28 (m, 2H), 2.30-2.16 (m, 3H), 2.05-1.94(m, 2H), 1.70 (s, 1H), 0.87 (d, J=6.5 Hz, 3H) ppm.

Example 45(S)-1-(4-(6-((4-((3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-3,5-difluorobenzyl)pyrrolidine-3-carbonitrile

This compound was synthesized according to the procedures described inExample 39, using (S)-pyrrolidine-3-carbonitrile (from Tyger) to replacemorpholine in Step 1. LCMS calc. for C₂₉H₃₃F₃N₇O (M+H)⁺ m/z=552.3.found: 552.3. ¹H NMR (400 MHz, DMSO-d6) δ 7.91 (t, J=9.0 Hz, 1H), 7.81(d, J=5.1 Hz, 1H), 7.76 (s, 1H), 7.57 (dd, J=8.6, 3.9 Hz, 1H), 7.23 (d,J=8.6 Hz, 2H), 6.83 (d, J=5.1 Hz, 1H), 5.63 (t, J=5.8 Hz, 1H), 4.77 (d,J=4.0 Hz, 1H), 4.62-4.45 (m, 2H), 3.74 (s, 2H), 3.26-3.14 (m, 2H),2.88-2.64 (m, 5H), 2.59-2.52 (m, 2H), 2.38-2.30 (m, 2H), 2.29-2.18 (m,3H), 2.06-1.95 (m, 1H), 1.69 (s, 1H), 0.87 (d, J=6.6 Hz, 3H) ppm.

Example 46(3R,4R,5S)-3-amino-1-(3-(((6-(2,6-difluoro-4-(((R)-3-fluoropyrrolidin-1-yl)methyl)phenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol

This compound was synthesized using similar procedures as described inExample 39, using (R)-3-fluoropyrrolidine (from Aldrich) to replacemorpholine in Step 1. LCMS calc. for C₂₈H₃₃F₄N₆O (M+H)⁺ m/z=545.3.found: 545.2. ¹H NMR (400 MHz, DMSO-d6) δ 7.91 (t, J=9.0 Hz, 1H), 7.81(d, J=5.1 Hz, 1H), 7.76 (s, 1H), 7.57 (dd, J=8.6, 3.9 Hz, 1H), 7.23 (d,J=8.6 Hz, 2H), 6.83 (d, J=5.1 Hz, 1H), 5.62 (t, J=5.7 Hz, 1H), 5.34-5.29(m, 1H), 5.21-5.15 (m, 1H), 4.76 (d, J=4.3 Hz, 1H), 4.59-4.44 (m, 2H),3.81-3.69 (m, 2H), 3.26-3.14 (m, 2H), 2.95-2.79 (m, 2H), 2.79-2.64 (m,4H), 2.47-2.38 (m, 1H), 2.34 (t, J=10.6 Hz, 1H), 2.29-2.09 (m, 2H),2.02-1.81 (m, 1H), 1.69 (br, 1H), 0.91-0.83 (m, 3H) ppm.

Example 47(3R,4R,5S)-3-amino-1-(3-(((6-(2,6-difluoro-4-(((S)-3-fluoropyrrolidin-1-yl)methyl)phenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol

This compound was synthesized according to the procedures described inExample 39, using (S)-3-fluoropyrrolidine (from Aldrich) to replacemorpholine in Step 1. LCMS calc. for C₂₈H₃₃F₄N₆O (M+H)⁺ m/z=545.3.found: 545.2.

Example 484-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-N-({6-[2,6-difluoro-4-(morpholin-4-ylmethyl)phenyl]-5-fluoropyridin-2-yl}methyl)pyridin-3-amine

Step 1. tert-Butyl((3S,5R)-1-{3-[({6-[2,6-difluoro-4-(morpholin-4-ylmethyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate

tert-Butyl[(3S,5R)-1-(3-{[(6-bromo-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(intermediate 2, 15.8 mg, 0.0320 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (2.5 mg, 0.0032 mmol), potassium phosphate (20 mg, 0.096mmol) and magnet bar were placed in a vial with septum. The vial wasthen evacuated and backfilled with nitrogen three times. 1,4-Dioxane(2.5 mL) and degassed water (0.3 mL) were added to the reaction mixture.Finally4-[3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]morpholine(17 mg, 0.051 mmol) was added and the reaction mixture was stirred at65° C. for 1 h. Then the reaction mixture was diluted with EtOAc. Theresulting solution was washed with brine, dried over Na₂SO₄ and thesolvent was evaporated. The resulting crude product was used in the nextstep without further purification. LCMS calc. for C₃₃H₄₂F₃N₆O₃ (M+H)⁺m/z=627.3. found: 627.3.

Step 2.4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-N-({6-[2,6-difluoro-4-(morpholin-4-ylmethyl)phenyl]-5-fluoropyridin-2-yl}methyl)pyridin-3-amine

tert-Butyl((3S,5R)-1-{3-[({6-[2,6-difluoro-4-(morpholin-4-ylmethyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate(20 mg, 0.032 mmol) was dissolved in methanol (2 mL). Then 4.0 Msolution of HCl in dioxane (1 mL, 4 mmol) was added to the reactionmixture. The reaction mixture was stirred at room temperature overnight.Then the reaction mixture was neutralized by addition of the ammoniasolution and purified by RP-HPLC (water XBridge C18 column, 30 mm×100mm, 5 m particle size, gradient elution with acetonitrile/watercontaining 0.1% NH₄OH, at flow rate of 60 mL/min). LCMS calc. forC₂₈H₃₄F₃N₆O (M+H)⁺ m/z=527.3. found: 527.3. ¹H NMR (400 MHz, DMSO-d6) δ7.93 (t, J=9.0 Hz, 1H), 7.82 (d, J=5.0 Hz, 1H), 7.80 (s, 1H), 7.60 (dd,J=8.7, 3.9 Hz, 1H), 7.25 (d, J=8.6 Hz, 2H), 6.82 (d, J=5.1 Hz, 1H), 5.69(t, J=5.5 Hz, 1H), 4.52 (qd, J=16.3, 5.3 Hz, 3H), 3.68-3.60 (m, 4H),3.60 (s, 2H), 3.15 (t, J=12.5 Hz, 2H), 2.76 (t, J=10.7 Hz, 1H),2.47-2.38 (m, 4H), 2.13 (t, J=10.5 Hz, 1H), 1.96 (t, J=11.0 Hz, 1H),1.86-1.57 (m, 2H), 0.76 (d, J=6.4 Hz, 3H), 0.74-0.65 (m, 1H) ppm.

Example 494-((3S,5R)-3-Amino-5-methylpiperidin-1-yl)-N-((6-(2,6-difluoro-4-((methylamino)methyl)phenyl)-5-fluoropyridin-2-yl)methyl)pyridin-3-amine

This compound was synthesized according to the procedures described inExample 48 and Example 39, using 2.0 M solution of methanamine in THF toreplace morpholine in Step 1 of Example 39. LCMS calc. for C₂₅H₃₀F₃N₆(M+H)⁺ m/z=471.3. found: 471.2.

Example 504-((3S,5R)-3-Amino-5-methylpiperidin-1-yl)-N-((6-(4-(azetidin-1-ylmethyl)-2,6-difluorophenyl)-5-fluoropyridin-2-yl)methyl)pyridin-3-amine

This compound was synthesized according to the procedures as describedin Example 48 and Example 39, using azetidine to replace morpholine inStep 1 of Example 39. LCMS calc. for C₂₇H₃₂F₃N₆ (M+H)⁺ m/z=497.3. found:497.3. ¹H NMR (400 MHz, DMSO-d6) δ 7.92 (t, J=9.0 Hz, 1H), 7.82 (d,J=5.0 Hz, 1H), 7.79 (s, 1H), 7.59 (dd, J=8.6, 3.9 Hz, 1H), 7.18 (d,J=8.7 Hz, 2H), 6.82 (d, J=5.1 Hz, 1H), 5.69 (t, J=5.4 Hz, 1H), 4.52 (qd,J=16.4, 5.6 Hz, 3H), 3.64 (s, 2H), 3.21 (t, J=7.0 Hz, 4H), 3.18-3.10 (m,2H), 2.84-2.72 (m, 1H), 2.13 (t, J=10.5 Hz, 1H), 2.04 (p, J=7.0 Hz, 2H),1.95 (t, J=11.0 Hz, 1H), 1.85-1.66 (m, 2H), 0.75 (d, J=6.5 Hz, 3H),0.73-0.66 (m, 1H) ppm.

Example 51(R)-1-(4-(6-((4-((3S,5R)-3-Amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-3,5-difluorobenzyl)pyrrolidin-3-ol

This compound was synthesized according to the procedures described inExample 48 and Example 39, using (R)-pyrrolidin-3-ol to replacemorpholine in Step 1 of Example 39. LCMS calc. for C₂₈H₃₄F₃N₆O (M+H)⁺m/z=527.3. found: 527.3. ¹H NMR (400 MHz, DMSO-d6) δ 7.93 (t, J=8.9 Hz,1H), 7.82 (d, J=5.0 Hz, 1H), 7.80 (s, 1H), 7.60 (dd, J=8.7, 3.8 Hz, 1H),7.24 (d, J=8.6 Hz, 2H), 6.82 (d, J=5.1 Hz, 1H), 5.70 (t, J=5.4 Hz, 1H),4.61-4.45 (m, 3H), 4.30-4.19 (m, 2H), 3.78-3.59 (m, 2H), 3.15 (t, J=11.1Hz, 1H), 2.82-2.62 (m, 4H), 2.49-2.44 (m, 1H), 2.40 (dd, J=9.6, 3.5 Hz,1H), 2.14 (t, J=10.5 Hz, 1H), 2.10-2.00 (m, 2H), 1.95 (t, J=11.1 Hz,1H), 1.86-1.66 (m, 1H), 1.64-1.53 (m, 1H), 0.76 (d, J=6.5 Hz, 3H),0.75-0.67 (m, 1H) ppm.

Example 52(S)-1-(4-(6-((4-((3S,5R)-3-Amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-3,5-difluorobenzyl)pyrrolidin-3-ol

This compound was synthesized according to the procedures described inExample 48 and Example 39, using (S)-pyrrolidin-3-ol to replacemorpholine in Step 1 of Example 39. LCMS calc. for C₂₈H₃₄F₃N₆O (M+H)⁺m/z=527.3. found: 527.3. ¹H NMR (400 MHz, DMSO-d6) δ 7.93 (t, J=8.9 Hz,1H), 7.83 (d, J=5.0 Hz, 1H), 7.81 (s, 1H), 7.60 (dd, J=8.7, 3.9 Hz, 1H),7.24 (d, J=8.6 Hz, 2H), 6.82 (d, J=5.1 Hz, 1H), 5.71 (t, J=5.3 Hz, 1H),4.64-4.41 (m, 3H), 4.31-4.18 (m, 1H), 3.81-3.57 (m, 2H), 3.24-3.09 (m,2H), 2.83-2.60 (m, 4H), 2.49-2.44 (m, 1H), 2.39 (dd, J=9.6, 3.6 Hz, 1H),2.14 (t, J=10.6 Hz, 1H), 2.04 (dq, J=14.3, 7.7 Hz, 2H), 1.94 (t, J=11.1Hz, 1H), 1.86-1.66 (m, 1H), 1.66-1.54 (m, 1H), 0.76 (d, J=6.5 Hz, 3H),0.74-0.66 (m, 1H) ppm.

Example 53(R)-1-(4-(6-((4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-3,5-difluorobenzyl)pyrrolidine-3-carbonitrile

This compound was synthesized according to the procedures described inExample 48 and Example 39, using (R)-pyrrolidine-3-carbonitrile toreplace morpholine in Step 1 of Example 39. LCMS calc. for C₂₉H₃₃F₃N₇(M+H)⁺ m/z=536.3. found: 536.3. ¹H NMR (400 MHz, DMSO-d6) δ 7.93 (t,J=9.0 Hz, 1H), 7.82 (d, J=5.1 Hz, 1H), 7.80 (s, 1H), 7.60 (dd, J=8.7,3.9 Hz, 1H), 7.25 (d, J=8.5 Hz, 2H), 6.82 (d, J=5.1 Hz, 1H), 5.70 (t,J=5.3 Hz, 1H), 4.69-4.45 (m, 3H), 3.76 (s, 2H), 3.16 (dd, J=19.2, 10.3Hz, 1H), 2.86-2.69 (m, 4H), 2.59-2.52 (m, 1H), 2.30-2.17 (m, 2H), 2.14(t, J=10.6 Hz, 1H), 2.06-1.93 (m, 3H), 1.85-1.64 (m, 2H), 0.77 (d, J=6.5Hz, 3H), 0.76-0.68 (m, 1H) ppm.

Example 54(S)-1-(4-(6-((4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-3,5-difluorobenzyl)pyrrolidine-3-carbonitrile

This compound was synthesized according to the procedures described inExample 48 and Example 39, using (S)-pyrrolidine-3-carbonitrile toreplace morpholine in Step 1 of Example 39. LCMS calc. for C₂₉H₃₃F₃N₇(M+H)⁺ m/z=536.3. found: 536.3. ¹H NMR (400 MHz, DMSO-d6) δ 7.93 (t,J=9.0 Hz, 1H), 7.83 (d, J=5.0 Hz, 1H), 7.80 (s, 1H), 7.60 (dd, J=8.7,3.9 Hz, 1H), 7.25 (d, J=8.6 Hz, 2H), 6.83 (d, J=5.1 Hz, 1H), 5.70 (t,J=5.4 Hz, 1H), 4.53 (qd, J=16.4, 5.5 Hz, 3H), 3.76 (s, 2H), 3.17 (dd,J=26.0, 8.3 Hz, 1H), 2.79 (tdd, J=14.2, 11.4, 5.2 Hz, 5H), 2.59-2.52 (m,1H), 2.29-2.19 (m, 2H), 2.16 (t, J=10.6 Hz, 1H), 2.05-1.93 (m, 3H), 1.78(dd, J=22.4, 12.1 Hz, 2H), 0.78 (d, J=6.5 Hz, 3H), 0.75-0.71 (m, 1H)ppmS.

Example 554-((3S,5R)-3-amino-5-methylpiperidin-1-yl)-N-((6-(2,6-difluoro-4-(((R)-3-fluoropyrrolidin-1-yl)methyl)phenyl)-5-fluoropyridin-2-yl)methyl)pyridin-3-amine

This compound was synthesized according to the procedures described inExample 48 and Example 39, using (R)-3-fluoropyrrolidine to replacemorpholine in Step 1 of Example 39. LCMS calc. for C₂₈H₃₃F₄N₆ (M+H)⁺m/z=529.3. found: 529.2.

Example 564-((3S,5R)-3-amino-5-methylpiperidin-1-yl)-N-((6-(2,6-difluoro-4-(((S)-3-fluoropyrrolidin-1-yl)methyl)phenyl)-5-fluoropyridin-2-yl)methyl)pyridin-3-amine

This compound was synthesized according to the procedures described inExample 48 and Example 39, using (S)-3-fluoropyrrolidine to replacemorpholine in Step 1 of Example 39. LCMS calc. for C₂₈H₃₃F₄N₆ (M+H)⁺m/z=529.3. found: 529.2.

Example 57(3R,4R,5S)-3-Amino-1-(3-{[(6-cyclohex-1-en-1-yl-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-4-ol

Step 1. tert-Butyl[(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-(3-{[(6-cyclohex-1-en-1-yl-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate

tert-Butyl((3R,4R,5S)-1-(3-{[(6-bromo-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(intermediate 1, 20.0 mg, 0.0320 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (2.5 mg, 0.0032 mmol), potassium phosphate (20 mg, 0.096mmol) and magnet bar were placed in a vial with septum. The vial wasthen evacuated and backfilled with nitrogen three times. 1,4-Dioxane(2.5 mL) and degassed water (0.3 mL) were added to the reaction mixture.Finally, 2-cyclohex-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(from Aldrich, 11 mg, 0.051 mmol) was added and the reaction mixture wasstirred at 65° C. for 1 h. Then the reaction mixture was diluted withEtOAc. The resulting solution was washed with brine, dried over Na₂SO₄and solvent evaporated. The resulting crude product was used in the nextstep without further purification. LCMS calc. for C₃₄H₅₃FN₅O₃Si (M+H)⁺m/z=626.4. found: 626.4.

Step 2.(3R,4R,5S)-3-Amino-1-(3-{[(6-cyclohex-1-en-1-yl-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-4-ol

tert-Butyl[(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-(3-{[(6-cyclohex-1-en-1-yl-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(20 mg, 0.032 mmol) was dissolved in methanol (2 mL). Then 4.0 Msolution of HCl in dioxane (1 mL, 4 mmol) was added to the reactionmixture. The reaction mixture was stirred at room temperature overnight.Then the reaction mixture was neutralized by addition of the ammoniasolution and purified by RP-HPLC (water XBridge C18 column, 30 mm×100mm, 5 m particle size, gradient elution with acetonitrile/watercontaining 0.1% NH₄OH, at flow rate of 60 mL/min). LCMS calc. forC₂₃H₃₁FN₅O (M+H)⁺ m/z=412.3. found: 412.3.

Example 584-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-N-[(6-cyclohexyl-5-fluoropyridin-2-yl)methyl]pyridin-3-amine

Step 1. tert-Butyl[(3S,5R)-1-(3-{[(6-cyclohex-1-en-1-yl-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate

tert-Butyl[(3S,5R)-1-(3-{[(6-bromo-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(Intermediate 2; 15.8 mg, 0.0320 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (2.5 mg, 0.0032 mmol), potassium phosphate (20 mg, 0.096mmol) and magnet bar were placed in a vial with septum. The vial wasthen evacuated and backfilled with nitrogen three times. 1,4-Dioxane(2.5 mL) and degassed water (0.3 mL) were added to the reaction mixture.Finally 2-cyclohex-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (11mg, 0.051 mmol) was added and the reaction mixture was stirred at 65° C.for 1 h. Then the reaction mixture was diluted with EtOAc. The resultingsolution was washed with brine, dried over Na₂SO₄ and solventevaporated. The resulting crude product was used in the next stepwithout further purification. LCMS calc. for C₂₈H₃₉FN₅O₂ (M+H)⁺m/z=496.3. found: 496.3.

Step 2. tert-Butyl[(3S,5R)-1-(3-{[(6-cyclohexyl-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate

To a stirred solution of tert-butyl[(3S,5R)-1-(3-{[(6-cyclohex-1-en-1-yl-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(16 mg, 0.032 mmol) in methanol (1.5 mL) was added 5 w % of Pd on carbon(3.1 mg, 0.0015 mmol). The vial containing reaction mixture was closedwith septum and was connected to a balloon with hydrogen. After stirringat room temperature overnight, reaction mixture was filtered through apad of diatomaceous earth and the solvent was evaporated under reducedpressure. The resulting crude product was used in the next step withoutfurther purification. LCMS calc. for C₂₈H₄₁FN₅O₂ (M+H)⁺ m/z=498.3.found: 498.3.

Step 3.4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-N-[(6-cyclohexyl-5-fluoropyridin-2-yl)methyl]pyridin-3-amine

tert-Butyl[(3S,5R)-1-(3-{[(6-cyclohexyl-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(16 mg, 0.032 mmol) was dissolved in methanol (2 mL). Then 4.0 Msolution of HCl in dioxane (1 mL, 4 mmol) was added to the reactionmixture. The reaction mixture was stirred at room temperature overnight.Then the reaction mixture was neutralized by addition of the ammoniasolution and purified by RP-HPLC (water XBridge C18 column, 30 mm×100mm, 5 μm particle size, gradient elution with acetonitrile/watercontaining 0.1% NH₄OH, at flow rate of 60 mL/min). LCMS calc. forC₂₃H₃₃FN₅ (M+H)⁺ m/z=398.3. found: 398.2.

Example 59(3R,4R,5S)-3-Amino-1-{3-[({6-[2,6-difluoro-4-(4-methoxytetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol

Step 1. 4-(3,5-Difluorophenyl)tetrahydro-2H-pyran-4-ol

Tetrahydro-4H-pyran-4-one (from Aldrich, 1.00 g, 9.99 mmol) and a magnetbar were placed in a vial. The vial was evacuated and backfilled withnitrogen three times. After addition of tetrahydrofuran (15 mL), thereaction mixture was cooled to 0° C. Then 0.5 M solution of(3,5-difluorophenyl)magnesium bromide in THF (22 mL, 11 mmol) was slowlyadded and the reaction mixture was stirred at room temperature for 16 h.After this time the reaction mixture was carefully quenched by theaddition of saturated solution of ammonium chloride. The product wasextracted with EtOAc. Combined organic fractions were washed with brine,dried over Na₂SO₄ and solvents were evaporated under reduced pressure.The resulting product was used in the next step without furtherpurification (1.2 g, 56%).

Step 2. 4-(3,5-Difluorophenyl)-4-methoxytetrahydro-2H-pyran

4-(3,5-Difluorophenyl)tetrahydro-2H-pyran-4-ol (400.0 mg, 1.867 mmol)was added to DMF (6.0 mL) and the reaction mixture was cooled to 0° C.Then NaH in mineral oil (60%, 90 mg, 2.2 mmol) was slowly added to thereaction mixture. After addition was complete, the reaction mixture wasstirred at 0° C. for 30 min. Then methyl iodide (350 μL, 5.6 mmol) wasslowly added and the reaction mixture was stirred at room temperatureovernight. After this time, water was added to the reaction and theproduct was extracted with EtOAc. Combined organic fractions were washedwith brine, dried over Na₂SO₄ and the solvents were evaporated underreduced pressure. The crude product was purified by Biotage Isolera togive the desired compound (183 mg, 43%).

Step 3.4-[3,5-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-methoxytetrahydro-2H-pyran

4-(3,5-Difluorophenyl)-4-methoxytetrahydro-2H-pyran (183 mg, 0.802 mmol)and a magnet bar were placed in a vial. The vial was evacuated andbackfilled with nitrogen three times. After addition of tetrahydrofuran(3.0 mL), the reaction mixture was cooled to −78° C. Then 2.5 M solutionof n-butyllithium in hexanes (640 μL, 1.6 mmol) was slowly added and thereaction mixture was stirred at −78° C. for 1 h. After this time2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (410 μL, 2.0 mmol)was slowly added. After stirring at −78° C. for 5 min, the reactionmixture was allowed to warm to room temperature and was stirred at roomtemperature for 1 h. After this time the reaction mixture was carefullyquenched by the addition of saturated solution of ammonium chloride. Theproduct was extracted with EtOAc. Combined organic fractions were washedwith brine, dried over Na₂SO₄ and solvents were evaporated under reducedpressure. The resulting product was used in the next step withoutfurther purification.

Step 4. tert-Butyl((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-{3-[({6-[2,6-difluoro-4-(4-methoxytetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate

tert-Butyl((3R,4R,5S)-1-(3-{[(6-bromo-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(intermediate 1, 20.0 mg, 0.0320 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (2.5 mg, 0.0032 mmol), potassium phosphate (20 mg, 0.096mmol) and magnet bar were placed in a vial with septum. The vial wasthen evacuated and backfilled with nitrogen three times. 1,4-Dioxane(2.5 mL) and degassed water (0.3 mL) were added to the reaction mixture.Finally,4-[3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-methoxytetrahydro-2H-pyran(18 mg, 0.051 mmol) was added and the reaction mixture was stirred at65° C. for 1 h. Then the reaction mixture was diluted with EtOAc. Theresulting solution was washed with brine, dried over Na₂SO₄ and solventevaporated. The resulting crude product was used in the next stepwithout further purification. LCMS calc. for C₄₀H₅₇F₃N₅O₅Si (M+H)⁺m/z=772.4. found: 772.3.

Step 5.(3R,4R,5S)-3-Amino-1-{3-[({6-[2,6-difluoro-4-(4-methoxytetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol

tert-Butyl((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-{3-[({6-[2,6-difluoro-4-(4-methoxytetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate(25 mg, 0.032 mmol) was dissolved in methanol (2 mL). Then 4.0 Msolution of HCl in dioxane (1 mL, 4 mmol) was added to the reactionmixture. The reaction mixture was stirred at room temperature overnight.Then the reaction mixture was neutralized by addition of the ammoniasolution and purified by RP-HPLC (water XBridge C18 column, 30 mm×100mm, 5 μm particle size, gradient elution with acetonitrile/watercontaining 0.1% NH₄OH, at flow rate of 60 mL/min). LCMS calc. forC₂₉H₃₅F₃N₅O₃(M+H)⁺ m/z=558.3. found: 558.2.

Example 604-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-N-({6-[2,6-difluoro-4-(4-methoxytetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)pyridin-3-amine

Step 1. tert-Butyl((3S,5R)-1-{3-[({6-[2,6-difluoro-4-(4-methoxytetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate

tert-Butyl[(3S,5R)-1-(3-{[(6-bromo-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(Intermediate 2; 15.8 mg, 0.0320 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (2.5 mg, 0.0032 mmol), potassium phosphate (20 mg, 0.096mmol) and magnet bar were placed in a vial with septum. The vial wasthen evacuated and backfilled with nitrogen three times. 1,4-Dioxane(2.5 mL) and degassed water (0.3 mL) were added to the reaction mixture.Finally4-[3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-methoxytetrahydro-2H-pyran(18 mg, 0.051 mmol) was added and the reaction mixture was stirred at65° C. for 1 h. Then the reaction mixture was diluted with EtOAc. Theresulting solution was washed with brine, dried over Na₂SO₄ and solventevaporated. The resulting crude product was used in the next stepwithout further purification. LCMS calc. for C₃₄H₄₃F₃N₅O₄(M+H)⁺m/z=642.3. found: 642.4.

Step 2.4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-N-({6-[2,6-difluoro-4-(4-methoxytetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)pyridin-3-amine

tert-Butyl((3S,5R)-1-{3-[({6-[2,6-difluoro-4-(4-methoxytetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate(21 mg, 0.032 mmol) was dissolved in methanol (2 mL). Then 4.0 Msolution of HCl in dioxane (1 mL, 4 mmol) was added to the reactionmixture. The reaction mixture was stirred at room temperature overnight.Then the reaction mixture was neutralized by addition of the ammoniasolution and purified by RP-HPLC (water XBridge C18 column, 30 mm×100mm, 5 m particle size, gradient elution with acetonitrile/watercontaining 0.1% NH₄OH, at flow rate of 60 mL/min). LCMS calc. forC₂₉H₃₅F₃N₅O₂(M+H)⁺ m/z=542.3. found: 542.2.

Example 61(3R,4R,5S)-3-Amino-1-{3-[({6-[2,6-difluoro-4-(4-fluorotetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol

Step 1. 4-(3,5-Difluorophenyl)-4-fluorotetrahydro-2H-pyran

To a solution of 4-(3,5-difluorophenyl)tetrahydro-2H-pyran-4-ol(Prepared in Example 59, Step 1; 400.0 mg, 1.867 mmol) in DCM (5.0 mL)was slowly added diethylaminosulfur trifluoride (270 μL, 2.0 mmol).After stirring at room temperature for 1 h the solvent was evaporatedunder reduced pressure and the crude product was purified by BiotageIsolera to give the desired compound (208 mg, 52%).

Step 2.4-[3,5-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-fluorotetrahydro-2H-pyran

4-(3,5-Difluorophenyl)-4-fluorotetrahydro-2H-pyran (208 mg, 0.962 mmol)and a magnet bar were placed in a vial. The vial was evacuated andbackfilled with nitrogen three times. After addition of tetrahydrofuran(3.0 mL), the reaction mixture was cooled to −78° C. Then 2.5 M solutionof n-butyllithium in hexanes (770 μL, 1.9 mmol) was slowly added and thereaction was stirred at −78° C. for 1 h. After this time2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (490 μL, 2.4 mmol)was slowly added to the reaction mixture. After stirring at −78° C. for5 min more, the reaction was allowed to warm to room temperature and wasstirred at room temperature for 1 h. After this time the reactionmixture was carefully quenched by the addition of saturated solution ofammonium chloride. The product was extracted with EtOAc. Combinedorganic fractions were washed with brine, dried over Na₂SO₄ and solventswere evaporated under reduced pressure. The resulting product was usedin the next step without further purification.

Step 3. tert-Butyl((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-{3-[({6-[2,6-difluoro-4-(4-fluorotetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate

tert-Butyl((3R,4R,5S)-1-(3-{[(6-bromo-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(Intermediate 1, 20.0 mg, 0.0320 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (2.5 mg, 0.0032 mmol), potassium phosphate (20 mg, 0.096mmol) and magnet bar were placed in a vial with septum. The vial wasthen evacuated and backfilled with nitrogen three times. 1,4-Dioxane(2.5 mL) and degassed water (0.3 mL) were added to the reaction mixture.Finally4-[3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-fluorotetrahydro-2H-pyran(18 mg, 0.051 mmol) was added and the reaction mixture was stirred at65° C. for 1 h. Then the reaction mixture was diluted with EtOAc. Theresulting solution was washed with brine, dried over Na₂SO₄ and solventevaporated. The resulting crude product was used in the next stepwithout further purification. LCMS calc. for C₃₉H₅₄F₄N₅O₄Si (M+H)⁺m/z=760.4. found: 760.4.

Step 4.(3R,4R,5S)-3-Amino-1-{3-[({6-[2,6-difluoro-4-(4-fluorotetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol

tert-Butyl((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-{3-[({6-[2,6-difluoro-4-(4-fluorotetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate(24 mg, 0.032 mmol) was dissolved in methanol (2 mL). Then 4.0 Msolution of HCl in dioxane (1 mL, 4 mmol) was added to the reactionmixture. The reaction mixture was stirred at room temperature overnight.Then the reaction mixture was neutralized by addition of the ammoniasolution and purified by RP-HPLC (water XBridge C18 column, 30 mm×100mm, 5 μm particle size, gradient elution with acetonitrile/watercontaining 0.1% NH₄OH, at flow rate of 60 mL/min). LCMS calc. forC₂₈H₃₂F₄N₅O₂(M+H)⁺ m/z=546.3. found: 546.3. ¹H NMR (400 MHz, DMSO-d6) δ7.93 (t, J=9.0 Hz, 1H), 7.82 (d, J=5.1 Hz, 1H), 7.79 (s, 1H), 7.60 (dd,J=8.7, 3.9 Hz, 1H), 7.40 (d, J=8.8 Hz, 2H), 6.85 (d, J=5.1 Hz, 1H), 5.73(t, J=5.6 Hz, 1H), 5.21 (d, J=4.4 Hz, 2H), 4.64-4.43 (m, 3H), 3.90 (dd,J=11.1, 5.0 Hz, 2H), 3.71 (t, J=11.0 Hz, 2H), 3.19 (d, J=10.7 Hz, 1H),2.95 (td, J=10.1, 4.4 Hz, 1H), 2.91-2.83 (m, 1H), 2.49-2.41 (m, 1H),2.38-2.12 (m, 4H), 1.91 (t, J=11.8 Hz, 2H), 1.80-1.64 (m, 1H), 0.86 (d,J=6.6 Hz, 3H) ppm.

Example 624-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-N-({6-[2,6-difluoro-4-(4-fluorotetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)pyridin-3-amine

Step 1. tert-Butyl((3S,5R)-1-{3-[({6-[2,6-difluoro-4-(4-fluorotetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate

tert-Butyl[(3S,5R)-1-(3-{[(6-bromo-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(intermediate 2, 15.8 mg, 0.0320 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (2.5 mg, 0.0032 mmol), potassium phosphate (20 mg, 0.096mmol) and magnet bar were placed in a vial with septum. The vial wasthen evacuated and backfilled with nitrogen three times. 1,4-Dioxane(2.5 mL) and degassed water (0.3 mL) were added to the reaction mixture.Finally4-[3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-fluorotetrahydro-2H-pyran(Prepared in Example 61, Step 2; 18 mg, 0.051 mmol) was added and thereaction mixture was stirred at 65° C. for 1 h. Then the reactionmixture was diluted with EtOAc. The resulting solution was washed withbrine, dried over Na₂SO₄ and solvent evaporated. The resulting crudeproduct was used in the next step without further purification. LCMScalc. for C₃₃H₄₀F₄N₅O₃(M+H)⁺ m/z=630.3. found: 630.3.

Step 2.4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-N-({6-[2,6-difluoro-4-(4-fluorotetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)pyridin-3-amine

tert-Butyl((3S,5R)-1-{3-[({6-[2,6-difluoro-4-(4-fluorotetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate(20 mg, 0.032 mmol) was dissolved in methanol (2 mL). Then 4.0 Msolution of HCl in dioxane (1 mL, 4 mmol) was added to the reactionmixture. The reaction mixture was stirred at room temperature overnight.Then the reaction mixture was neutralized by addition of the ammoniasolution and purified by RP-HPLC (water XBridge C18 column, 30 mm×100mm, 5 m particle size, gradient elution with acetonitrile/watercontaining 0.1% NH₄OH, at flow rate of 60 mL/min). LCMS calc. forC₂₈H₃₂F₄N₅O (M+H)⁺ m/z=530.3. found: 530.2.

Example 63(3R,4R,5S)-3-Amino-1-{3-[({6-[2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol

Step 1. 4-(3,5-Difluorophenyl)-3,6-dihydro-2H-pyran

1-Bromo-3,5-difluorobenzene (0.80 g, 4.14 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (326 mg, 0.414 mmol), potassium phosphate (2.59 g, 12.4mmol) and magnet bar were placed in a vial with septum. The vial wasthen evacuated and backfilled with nitrogen three times. 1,4-Dioxane (10mL) and degassed water (1 mL) were added. Finally,4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran(Sigma-Aldrich, 1.05 g, 4.99 mmol) was added and the reaction mixturewas stirred at 65° C. for 1 h. Then the reaction mixture was dilutedwith EtOAc. The resulting solution was washed with brine, dried overNa₂SO₄ and solvent evaporated. The crude product was purified by BiotageIsolera to give the desired compound (700 mg, 86%).

Step 2. 4-(3,5-Difluorophenyl)tetrahydro-2H-pyran

To a stirred solution of 4-(3,5-difluorophenyl)-3,6-dihydro-2H-pyran(0.700 g, 3.57 mmol) in methanol (10 mL) was added 5 w % of Pd on carbon(31 mg, 0.015 mmol). Vial containing the reaction mixture was closedwith septum and was connected to a balloon with hydrogen. After stirringat room temperature overnight, the reaction was filtered through a padof diatomaceous earth and the solvent was evaporated under reducedpressure. The resulting crude product was used in the next step withoutfurther purification (700 mg, 99%).

Step 3. 2-(2,6-Difluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl)-4, 4,5,5-tetramethyl-1,3,2-dioxaborolane

4-(3,5-Difluorophenyl)tetrahydro-2H-pyran (700 mg, 2.2 mmol) and amagnet bar were placed in a vial. The vial was evacuated and backfilledwith nitrogen three times. After addition of tetrahydrofuran (8 mL), thereaction mixture was cooled to −78° C. Then 2.5 M solution ofn-butyllithium in hexanes (1.22 mL, 3.0 mmol) was slowly added and thereaction mixture was stirred at −78° C. for 1 h. After this time2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (715 μL, 3.5 mmol)was slowly added to the reaction mixture. After stirring at −78° C. for5 min more, the reaction was allowed to warm to room temperature and wasstirred at room temperature for 1 h. After this time the reactionmixture was carefully quenched by the addition of saturated solution ofammonium chloride. The product was extracted with EtOAc. Combinedorganic fractions were washed with brine, dried over Na₂SO₄ and solventswere evaporated under reduced pressure. The resulting product was usedin the next step without further purification.

Step 4. tert-Butyl((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-{3-[({6-[2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate

tert-Butyl((3R,4R,5S)-1-(3-{[(6-bromo-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(intermediate 1, 20.0 mg, 0.0320 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (2.5 mg, 0.0032 mmol), potassium phosphate (20 mg, 0.096mmol) and magnet bar were placed in a vial with septum. The vial wasthen evacuated and backfilled with nitrogen three times. 1,4-Dioxane(2.5 mL) and degassed water (0.3 mL) were added to the reaction mixture.Finally2-(2,6-Difluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(17 mg, 0.051 mmol) was added and the reaction mixture was stirred at65° C. for 1 h. Then the reaction mixture was diluted with EtOAc. Theresulting solution was washed with brine, dried over Na₂SO₄ and solventevaporated. The resulting crude product was used in the next stepwithout further purification. LCMS calc. for C₃₉H₅₅F₃N₅O₄Si (M+H)⁺m/z=742.4. found: 742.3.

Step 5.(3R,4R,5S)-3-Amino-1-{3-[({6-[2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol

tert-Butyl((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-{3-[({6-[2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate(24 mg, 0.032 mmol) was dissolved in methanol (2 mL). Then 4.0 Msolution of HCl in dioxane (1 mL, 4 mmol) was added to the reactionmixture. The reaction mixture was stirred at room temperature overnight.Then the reaction mixture was neutralized by addition of the ammoniasolution and purified by RP-HPLC (water XBridge C18 column, 30 mm×100mm, 5 μm particle size, gradient elution with acetonitrile/watercontaining 0.1% NH₄OH, at flow rate of 60 mL/min). LCMS calc. forC₂₈H₃₃F₃N₅O₂(M+H)⁺ m/z=528.3. found: 528.3. ¹H NMR (400 MHz, DMSO-d6) δ7.90 (t, J=9.0 Hz, 1H), 7.80 (d, J=5.1 Hz, 1H), 7.77 (s, 1H), 7.57 (dd,J=8.6, 3.8 Hz, 1H), 7.21 (d, J=9.0 Hz, 2H), 6.83 (d, J=5.1 Hz, 1H), 5.63(t, J=5.9 Hz, 1H), 4.74 (d, J=4.6 Hz, 1H), 4.61-4.45 (m, 2H), 4.02-3.92(m, 2H), 3.52-3.40 (m, 2H), 3.19 (td, J=9.5, 3.0 Hz, 2H), 2.92 (t,J=11.4 Hz, 1H), 2.76-2.62 (m, 2H), 2.34 (t, J=10.8 Hz, 1H), 2.21 (t,J=11.6 Hz, 1H), 1.87-1.52 (m, 7H), 0.84 (d, J=6.6 Hz, 3H) ppm.

Example 644-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-N-({6-[2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)pyridin-3-amine

Step 1. tert-Butyl((3S,5R)-1-{3-[({6-[2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate

tert-Butyl[(3S,5R)-1-(3-{[(6-bromo-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(Intermediate 2, 15.8 mg, 0.0320 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (2.5 mg, 0.0032 mmol), potassium phosphate (20 mg, 0.096mmol) and magnet bar were placed in a vial with septum. The vial wasthen evacuated and backfilled with nitrogen three times. 1,4-Dioxane(2.5 mL) and degassed water (0.3 mL) were added to the reaction mixture.Finally2-(2,6-Difluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Prepared in Example 63, Step 3; 17 mg, 0.051 mmol) was added and thereaction mixture was stirred at 65° C. for 1 h. Then the reactionmixture was diluted with EtOAc. The resulting solution was washed withbrine, dried over Na₂SO₄ and solvent evaporated. The resulting crudeproduct was used in the next step without further purification. LCMScalc. for C₃₃H₄₁F₃N₅O₃(M+H)⁺ m/z=612.3. found: 612.3.

Step 2.4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-N-({6-[2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)pyridin-3-amine

tert-Butyl((3S,5R)-1-{3-[({6-[2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl)}methyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate(20 mg, 0.032 mmol) was dissolved in methanol (2 mL). Then 4.0 Msolution of HCl in dioxane (1 mL, 4 mmol) was added to the reactionmixture. The reaction mixture was stirred at room temperature overnight.Then the reaction mixture was neutralized by addition of the ammoniasolution and purified by RP-HPLC (water XBridge C18 column, 30 mm×100mm, 5 m particle size, gradient elution with acetonitrile/watercontaining 0.1% NH₄OH, at flow rate of 60 mL/min). LCMS calc. forC₂₈H₃₃F₃N₅O (M+H)⁺ m/z=512.3. found: 512.3. ¹H NMR (400 MHz, DMSO-d6) δ7.93 (t, J=8.9 Hz, 1H), 7.82 (d, J=5.0 Hz, 1H), 7.80 (s, 1H), 7.60 (dd,J=8.7, 3.9 Hz, 1H), 7.24 (d, J=9.2 Hz, 2H), 6.81 (d, J=5.1 Hz, 1H), 5.73(t, J=5.4 Hz, 1H), 4.52 (qd, J=16.4, 5.3 Hz, 2H), 3.99 (d, J=10.6 Hz,2H), 3.46 (td, J=11.2, 3.4 Hz, 2H), 3.21-3.07 (m, 2H), 2.94 (dq, J=10.2,5.3 Hz, 1H), 2.83-2.71 (m, 1H), 2.14 (t, J=10.5 Hz, 1H), 1.94 (t, J=11.1Hz, 1H), 1.86-1.56 (m, 7H), 0.79-0.66 (m, 4H) ppm.

Example 654-((3S,5R)-3-Amino-5-(trifluoromethyl)piperidin-1-yl)-N-((6-(2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl)-5-fluoropyridin-2-yl)methyl)pyridin-3-amine

Step 1. tert-butyl((3S,5R)-1-(3-(((6-(2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl)carbamate

tert-butyl((3S,5R)-1-(3-(((6-bromo-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl)carbamate(intermediate 3, 17.5 mg, 0.0320 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (2.5 mg, 0.0032 mmol), potassium phosphate (20 mg, 0.096mmol) and magnet bar were placed in a vial with septum. The vial wasthen evacuated and backfilled with nitrogen three times. 1,4-Dioxane(2.5 mL) and degassed water (0.3 mL) were added to the reaction mixture.Finally2-(2,6-Difluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Prepared in Example 63, Step 3; 17 mg, 0.051 mmol) was added and thereaction mixture was stirred at 65° C. for 1 h. Then the reactionmixture was diluted with EtOAc. The resulting solution was washed withbrine, dried over Na₂SO₄ and solvent evaporated. The resulting crudeproduct was used in the next step without further purification. LCMScalc. for C₃₃H₃₈F₆N₅O₃(M+H)⁺ m/z=666.3. found: 666.2.

Step 2.4-((3S,5R)-3-Amino-5-(trifluoromethyl)piperidin-1-yl)-N-((6-(2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl)-5-fluoropyridin-2-yl)methyl)pyridin-3-amine

tert-Butyl((3S,5R)-1-(3-(((6-(2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl)carbamate(21 mg, 0.032 mmol) was dissolved in methanol (2 mL). Then 4.0 Msolution of HCl in dioxane (1 mL, 4 mmol) was added to the reactionmixture. The reaction mixture was stirred at room temperature overnight.Then the reaction mixture was neutralized by addition of the ammoniasolution and purified by RP-HPLC (water XBridge C18 column, 30 mm×100mm, 5 μm particle size, gradient elution with acetonitrile/watercontaining 0.1% NH₄OH, at flow rate of 60 mL/min). LCMS calc. forC₂₈H₃₀F₆N₅O (M+H)⁺ m/z=566.2. found: 566.2.

Example 664-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]-N-{[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}pyridin-3-amine

Step 1. Methyl 6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylate

To a screw-cap vial equipped with a magnetic stir bar, methyl6-bromo-5-fluoropyridine-2-carboxylate (Frontier Scientific, 200.2 mg,0.8555 mmol) was added followed by the addition of2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Combi-Blocks, 310.2 mg, 1.292 mmol), andbis(tri-tert-butylphosphine)palladium (87.5 mg, 0.171 mmol). The vialwas sealed with a PTFE-lined septum, evacuated and backfilled withnitrogen three times. 1,4-Dioxane (3.0 mL) was added via a syringe,followed by the addition of DIPEA (0.30 mL, 1.7 mmol) and deoxygenatedwater (0.1 mL). The reaction mixture was heated at 100° C. for 2 h andwas then allowed to cool to room temperature. The reaction mixture wasdiluted with EtOAc (40 mL), washed with water (40 mL) and brine (40 mL),then dried over Na₂SO₄, and concentrated under reduced pressure. Theresulting residue was purified by chromatography on silica gel (gradientelution with 0-50% EtOAc in hexanes) to give the sub-title compound as awhite solid (210.2 mg, 92%). LCMS calc. for C₁₃H₉F₃NO₂ (M+H)⁺:m/z=268.1. found 268.0.

Step 2. 6-(2,6-Difluorophenyl)-5-fluoropyridine-2-carboxylic acid

To a mixture of methyl6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylate (210.2 mg, 0.7867mmol) and lithium hydroxide, monohydrate (162 mg, 3.86 mmol), THF (3.0mL) was added followed by the addition of water (1.0 mL). The reactionmixture was heated at 50° C. for 3 h. The reaction mixture was thencooled to 0° C., and 1 M HCl was added slowly until the pH reached 2.The reaction mixture was then diluted with water (20 mL), extracted withEtOAc (3×20 mL) and the combined organic layers were washed with brine(30 mL), dried over Na₂SO₄, and concentrated under reduced pressure toyield the sub-title compound as a white solid (162.1 mg, 81%). LCMScalc. for C₁₂H₇F₃NO₂ (M+H)⁺: m/z=254.0. found 254.0.

Step 3: [6-(2,6-Difluorophenyl)-5-fluoropyridin-2-yl]methanol

To a mixture of 6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylicacid (2.00 g, 7.9 mmol) and triethylamine (1.16 mL, 8.3 mmol) intetrahydrofuran (38.4 mL) was slowly added isobutyl chloroformate (1.08mL, 8.3 mmol). The reaction mixture was stirred at room temperature for1 h. The precipitate was then collected by filtration. The filtrate wascooled in an ice bath and a solution of sodium borohydride (0.60 g, 2.0mmol) in water (10.0 mL) was added dropwise. The reaction mixture wasstirred for 1 h at room temperature, and then quenched with NaHCO₃solution, extracted with EtOAc, washed with brine. The combined organiclayers were filtered, dried over Na₂SO₄ and concentrated to give thedesired product as white powders (1.82 g, 96%). LCMS calc. for C₁₂H₉F₃NO(M+H)⁺: m/z=240.2. Found: 240.1.

Step 4: 6-(2,6-Difluorophenyl)-5-fluoropyridine-2-carbaldehyde

To a stirred solution of[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methanol (945 mg, 3.95mmol) in DCM (25.3 mL) at 0° C. were added pyridine (0.38 mL, 4.7 mmol)and Dess-Martin periodinane (1.76 g, 4.15 mmol). The reaction mixturewas stirred for 16 h at room temperature, at which time full conversionof the starting material to the aldehyde product was detected by LCMS.NaHCO₃ and Na₂S₂O₃ aqueous solutions were added and the resultingmixture was stirred for 30 min. The reaction mixture was extracted withDCM, dried and purified by Biotage column to give the desired product(675 mg, 72%) as white powders. LCMS calc. for C₁₂H₇F₃NO (M+H)⁺:m/z=238.0. Found: 238.2.

Step 5. tert-Butyl{(1S,3R,5S)-3-[3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}amino)pyridin-4-yl]-5-methylcyclohexyl}carbamate

tert-Butyl[(1S,3R,5S)-3-(3-aminopyridin-4-yl)-5-methylcyclohexyl]carbamate(Intermediate 6, peak 2; 69.4 mg, 0.227 mmol) and6-(2,6-difluorophenyl)-5-fluoropyridine-2-carbaldehyde (62.0 mg, 0.261mmol) were dissolved in toluene (1.4 mL) and 1 drop of acetic acid wasadded. The reaction mixture was heated at 100° C. for 2 h. After coolingto room temperature, the solvent was evaporated under reduced pressureand methanol (1.4 mL) was added. To the reaction mixture was addedsodium tetrahydroborate (17 mg, 0.45 mmol) and the resulting reactionmixture was stirred for 30 min. The reaction mixture was quenched withwater and NaHCO3. The layers were separated and the aqueous layer wasextracted with EtOAc. The combined organic phases were washed withbrine, dried over Na₂SO₄, filtered and concentrated. The crude was usedin the next step without further purification.

Step 6.4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]-N-{[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}pyridin-3-amine

tert-Butyl {(1 S,3R,5S)-3-[3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}amino)pyridin-4-yl]-5-methylcyclohexyl}carbamate(140 mg, 0.266 mmol) was dissolved in DCM (6 mL) and trifluoroaceticacid (6 mL) was added. The reaction mixture was stirred for 1 h. Afterremoving the solvent under reduced pressure, the residue was dissolvedin methanol and purified with prep-LCMS (XBridge C18 column, gradientelution with acetonitrile/water containing 0.1% ammonium hydroxide, atflow rate of 60 mL/min) to give the desired product as white solid (10.5mg, 9%). LCMS calc. for C₂₄H₂₆F₃N₄ (M+H)⁺: m/z=427.2. Found: 427.1.

Example 671-(4-{6-[({4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)cyclobutanol

Step 1. tert-Butyl((1S,3R,5S)-3-{3-[({6-[2,6-difluoro-4-(1-hydroxycyclobutyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylcyclohexyl)carbamate

tert-Butyl[(1S,3R,5S)-3-(3-aminopyridin-4-yl)-5-methylcyclohexyl])carbamate(Intermediate 6, peak 2; 37.2 mg, 0.122 mmol) and6-[2,6-difluoro-4-(1-hydroxycyclobutyl)phenyl]-5-fluoropyridine-2-carbaldehyde(Prepared in Example 2; 43.0 mg, 0.140 mmol) were dissolved in toluene(0.75 mL) and a drop of acetic acid was added. The reaction mixture washeated at 100° C. for 2 h. After cooling to room temperature, thesolvent was evaporated under reduced pressure and methanol (0.8 mL) wasadded. To the reaction mixture was added sodium tetrahydroborate (9.2mg, 0.24 mmol) and the resulting reaction mixture was stirred for 30min. The reaction was quenched with water and NaHCO₃. The layers wereseparated and the aqueous layer was extracted with EtOAc. The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andconcentrated. The crude residue was used in the next step withoutfurther purification.

Step 2.1-(4-{6-[({4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)cyclobutanol

The crude residue from last step was treated with 1:1 TFA/DCM (2 mL) for1 h. The solvent was evaporated under reduced pressure and the resultantresidue was dissolved in methanol and purified with prep-LCMS (XBridgeC18 column, gradient elution with acetonitrile/water containing 0.1%ammonium hydroxide, at flow rate of 60 mL/min) to give the desiredproduct as white solid (25 mg, 41%). LCMS calc. for C₂₈H₃₂F₃N₄O (M+H)⁺:m/z=497.2. Found: 497.2.

Example 684-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]-N-{[6-(2,6-difluoro-4-morpholin-4-ylphenyl)-5-fluoropyridin-2-yl]methyl}pyridin-3-amine

Step 1. Methyl6-(2,6-difluoro-4-morpholin-4-ylphenyl)-5-fluoropyridine-2-carboxylate

Methyl 6-bromo-5-fluoropyridine-2-carboxylate (250 mg, 1.1 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (84 mg, 0.11 mmol) and K₃PO₄ (680 mg, 3.2 mmol) were placed in avial with septum. The vial was then evacuated and backfilled withnitrogen three times. 1,4-Dioxane (8.1 mL) and degassed water (3 mL)were added, followed by4-[3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]morpholine(Prepared in Example 32, Step 2, 450 mg, 1.4 mmol). The reaction wasstirred at 55° C. for 1 h. The reaction mixture was diluted with EtOAcand washed with brine, dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by silica gel column to give the desired product(0.27 g, 72%). LCMS calc. for C₁₇H₁₆F₃N₂O₃(M+H)⁺: m/z=353.1. Found:353.1.

Step 2.6-(2,6-Difluoro-4-morpholin-4-ylphenyl)-5-fluoropyridine-2-carboxylicacid

A mixture of methyl6-(2,6-difluoro-4-morpholin-4-ylphenyl)-5-fluoropyridine-2-carboxylate(272 mg, 0.772 mmol), 1.0 M sodium hydroxide in water (3.1 mL, 3.1 mmol)in THF (8 mL)/methanol (6 mL) was stirred at r.t. for 1 h. The reactionmixture was acidified by the addition of 1M HCl. The aqueous layer wasextracted with EtOAc. The combined organic layers were washed withbrined, dried and concentrated to give the desired product which wasused in the next step without further purification. LCMS calc. forC₁₆H₁₄F₃N₂O₃(M+H)⁺: m/z=339.1. Found: 339.0.

Step 3.[6-(2,6-Difluoro-4-morpholin-4-ylphenyl)-5-fluoropyridin-2-yl]methanol

To a mixture of6-(2,6-difluoro-4-morpholin-4-ylphenyl)-5-fluoropyridine-2-carboxylicacid (242 mg, 0.715 mmol) and triethylamine (105 μL, 0.751 mmol) wasslowly added isobutyl chloroformate (97 μL, 0.75 mmol). The reactionmixture was stirred at room temperature for 1 h. The precipitate wasthen collected by filtration. The filtrate was cooled in an ice bath anda solution of sodium borohydride (54 mg, 1.4 mmol) in water (0.3 mL) wasadded dropwise. The reaction mixture was stirred for 1 h at roomtemperature, and then quenched with NaHCO₃ solution, extracted withEtOAc. The combined organic layers were washed with brine, dried overNa₂SO₄ and concentrated to give the desired product which was used inthe next step without further purification. LCMS calc. forC₁₆H₁₆F₃N₂O₂(M+H)⁺: m/z=325.1. Found: 325.1.

Step 4.6-(2,6-Difluoro-4-morpholin-4-ylphenyl)-5-fluoropyridine-2-carbaldehyde

To a stirred solution of[6-(2,6-difluoro-4-morpholin-4-ylphenyl)-5-fluoropyridin-2-yl]methanol(226 mg, 0.697 mmol) in DCM (5 mL) at 0° C. were added pyridine (68 μL,0.84 mmol) and Dess-Martin periodinane (310 mg, 0.732 mmol). Thereaction mixture was stirred for 16 h at r.t. The reaction mixture wasdiluted with ether and solution of NaHCO₃ and Na₂S₂₀₃ and the resultingmixture was stirred for 30 min. The layers were separated and theaqueous layer was extracted with ether. The extracts were combined,dried and concentrated. The residue was purified by flashchromatographyto give the desired product (0.19 g, 86%). LCMS calc. forC₁₆H₁₄F₃N₂O₂(M+H)⁺: m/z=323.1. Found: 323.1.

Step 5. tert-Butyl{(1S,3R,5S)-3-[3-({[6-(2,6-difluoro-4-morpholin-4-ylphenyl)-5-fluoropyridin-2-yl]methyl}amino)pyridin-4-yl]-5-methylcyclohexyl}carbamate

tert-Butyl[(1S,3R,5S)-3-(3-aminopyridin-4-yl)-5-methylcyclohexyl]carbamate(Intermediate 6, peak 2; 16.5 mg, 0.054 mmol) and6-(2,6-difluoro-4-morpholin-4-ylphenyl)-5-fluoropyridine-2-carbaldehyde(20.0 mg, 0.062 mmol) were dissolved in toluene (0.4 mL) and a drop ofAcOH was added. The reaction mixture was heated at 100° C. for 2 h.After cooling to room temperature, the solvent was evaporated underreduced pressure and methanol (0.4 mL) was added. To the reactionmixture was added sodium tetrahydroborate (4.1 mg, 0.11 mmol) and theresulting reaction mixture was stirred for 30 min. The reaction wasquenched with water and NaHCO₃. The layers were separated and theaqueous layer was extracted with EtOAc. The combined organic phases werewashed with brine, dried over Na₂SO₄, filtered and concentrated. Thecrude residue was used in the next step without further purification.

Step 6.4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]-N-{[6-(2,6-difluoro-4-morpholin-4-ylphenyl)-5-fluoropyridin-2-yl]methyl}pyridin-3-amine

The crude product from last step was treated with 1:1 TFA/DCM (2 mL) for1 h. The solvent was evaporated under reduced pressure and the residuewas dissolved in methanol and purified with prep-LCMS (XBridge C18column, gradient elution with acetonitrile/water containing 0.1%ammonium hydroxide, at flow rate of 60 mL/min) to give the desiredproduct as white solid (11 mg, 40%). LCMS calc. for C₂₈H₃₃F₃N₅O (M+H)⁺:m/z=512.3. Found: 512.2.

Example 69N-{[5-Amino-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]methyl}-4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-amine

Step 1. (3S,5R)-5-Methyl-1-(3-nitropyridin-4-yl)piperidin-3-amine

To a solution of tert-butyl[(3S,5R)-5-methyl-1-(3-nitropyridin-4-yl)piperidin-3-yl]carbamate(Prepared in Intermediate 2, Step 5; 2.10 g, 6.24 mmol) in DCM (28 mL)was added 4.0 M hydrogen chloride in dioxane (12.5 mL, 49.9 mmol). Theresulting mixture was stirred at room temperature for 4 h. The solventwas removed under reduced pressure and the solid was used in the nextstep. LCMS calc. for C₁₁H₁₇N₄O₂ (M+H)⁺: m/z=237.1. Found: 237.2.

Step 2. Benzyl[(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate

To a solution of(3S,5R)-5-methyl-1-(3-nitropyridin-4-yl)piperidin-3-amine (1.47 g, 6.22mmol) in DCM (20 mL) was added DIPEA (3.25 mL, 18.7 mmol), followed bybenzyl chloroformate (1.33 mL, 9.33 mmol) at 0° C. After stirring for 1h, the solution was diluted with water. The organic phase was separatedand concentrated under reduced pressure. The residue was dissolved inacetic acid (20 mL) and iron (2.8 g, 50 mmol) was added to the resultantreaction mixture. The reaction mixture was heated at 60° C. for 2 h. Thereaction mixture was filtered through a pad of diatomaceous earth andwashed with EtOAc. The solvent was removed under reduced pressure andthe residue was dissolved in methanol and purified with prep-LCMS(XBridge C18 column, gradient elution with acetonitrile/water containing0.05% TFA, at flow rate of 60 mL/min) give the desired product (0.32 g,15%) as an orange oil. LCMS calc. for C₁₉H₂₅N₄O₂ (M+H)⁺: m/z=341.2.Found: 341.2.

Step 3. Methyl 5-amino-2-bromo-1,3-thiazole-4-carboxylate

To a solution of methyl 5-amino-1,3-thiazole-4-carboxylate (J & WPharmLab, 10.0 g, 63.2 mmol) in THF (100 mL), N-bromosuccinimide (12.0g, 67.4 mmol) was added portion-wise. After stirring at room temperaturefor 1 h, the reaction mixture was filtered to give a first crop ofproduct as a pink solid (9.8 g). The filtrate was concentrated underreduced pressure. The resulting residue was triturated with EtOAc (15mL) and filtered to give a second crop of product as a pink solid (5.0g, total yield: 99%). LCMS calc. for C₅H₆BrN₂O₂S (M+H)⁺: m/z=236.9.found 237.0.

Step 4. Methyl2-bromo-5-[(tert-butoxycarbonyl)amino]-1,3-thiazole-4-carboxylate

To a solution of methyl 5-amino-2-bromo-1,3-thiazole-4-carboxylate (14.8g, 62.4 mmol) in THF (100 mL), di-tert-butyl dicarbonate (18.0 g, 82.2mmol), DMAP (1.5 g, 13 mmol) and triethylamine (17.6 mL, 126 mmol) wereadded. After stirring at room temperature for 16 h, the reaction mixturewas diluted with EtOAc (400 mL) and washed with water (2×250 mL). Theorganic layer was washed with brine (250 mL), dried over Na₂SO₄, andconcentrated under reduced pressure. The resulting residue was purifiedby chromatography on silica gel (gradient elution with 0-50% EtOAc inhexanes) to give the sub-title compound as a white solid (15.1 g, 72%).LCMS calc. for C₁₀H₁₄BrN₂O₄S (M+H)⁺: m/z=337.0. found 337.0.

Step 5. Methyl5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylate

To a round bottom flask equipped with a magnetic stir bar, methyl2-bromo-5-[(tert-butoxycarbonyl)amino]-1,3-thiazole-4-carboxylate (9.60g, 28.5 mmol) was added, followed by the addition of2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Combi-Blocks, 8.88 g, 37.0 mmol) andbis(tri-tert-butylphosphine)palladium (2.30 g, 4.50 mmol). The flask wassealed with a rubber septum, and evacuated and backfilled with nitrogenthree times. 1,4-Dioxane (40.0 mL) was added via a syringe, followed bythe addition of DIPEA (9.6 mL, 55 mmol) and deoxygenated water (2.0 mL).The resulting reaction mixture was heated at 100° C. for 1 h. Aftercooling to room temperature, the reaction mixture was diluted with EtOAc(200 mL) and washed with water (100 mL) and brine (200 mL), then driedover Na₂SO₄, and concentrated under reduced pressure. The resultingresidue was purified by chromatography on silica gel (0-100% EtOAc inhexanes) to give the sub-title compound as a white solid (9.80 g, 93%).LCMS calc. for C₁₆H₁₇F₂N₂O₄S (M+H)⁺: m/z=371.1. found 371.0.

Step 6.5-[(tert-Butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylicacid

To a suspension of methyl5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylate(6.99 g, 18.9 mmol) in MeOH (50.0 mL), lithium hydroxide monohydrate(5.24 g, 125 mmol) was added, followed by water (50.0 mL). The reactionmixture was heated at 60° C. for 5 h. The reaction mixture was thencooled to 0° C., and 6 M HCl was added slowly until the pH reached 2.The resulting solid was collected by filtration and the filter cake waswashed with water (50 mL) and MeOH/water (1:1, 50 mL) to provide thesub-title compound as a yellow solid (6.59 g, 98%). LCMS calc. forC₁₅H₁₅F₂N₂O₄S (M+H)⁺: m/z=357.1. found 357.0.

Step 7. tert-Butyl(2-(2,6-difluorophenyl)-4-{[methoxy(methyl)amino]carbonyl}-1,3-thiazol-5-yl)carbamate

To a solution of5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylicacid (2.51 g, 7.04 mmol) and N, O-dimethylhydroxylamine hydrochloride(0.656 g, 6.73 mmol) in DMF (20 mL) was addedN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (3.12 g, 8.22 mmol) and DIPEA (3.8 mL, 22 mmol). Thereaction mixture was stirred at room temperature overnight, and thendiluted with water, extracted with DCM. The combined organic layers weredried over Na₂SO₄, filtered and concentrated. The residue was purifiedwith flash chromatography (gradient elution with 0-30% EtOAc in hexanes)to give the desired product (2.14 g, 80%). LCMS calc. for C₁₇H₂₀F₂N₃O₄S(M+H)⁺: m/z=400.1. Found: 400.1.

Step 8. tert-Butyl[2-(2,6-difluorophenyl)-4-formyl-1,3-thiazol-5-yl]carbamate

A solution of tert-butyl(2-(2,6-difluorophenyl)-4-{[methoxy(methyl)amino]carbonyl}-1,3-thiazol-5-yl)carbamate(322 mg, 0.806 mmol) in THF (2.6 mL) was slowly added to 1.0 M lithiumtetrahydroaluminate in THF (0.846 mL, 0.846 mmol) at 0° C. The reactionmixture was allowed to warm to room temperature, and then stirred atroom temperature for 1 hour. The reaction was carefully quenched withsaturated aqueous Na₂SO₄ solution, and then extracted with EtOAc. Thecombined organic layers were washed with brine, dried and concentrated.The residue was purified with flash chromatography to give the desiredproduct as white solid (0.19 g, 69%). LCMS calc. for C₁₅H₁₅F₂N₂O₃S(M+H)⁺: m/z=341.1. Found: 341.0.

Step 5. 5-Amino-2-(2,6-difluorophenyl)-1,3-thiazole-4-carbaldehyde

To a stirred solution of tert-butyl[2-(2,6-difluorophenyl)-4-formyl-1,3-thiazol-5-yl]carbamate (190 mg,0.56 mmol) in DCM (0.5 mL) was added trifluoroacetic acid (0.5 mL, 6mmol). The resulting red solution was stirred at room temperature for 1h. The reaction mixture was concentrated, and the resultant residue wasdiluted with methanol and purified with prep-LCMS (XBridge C18 column,gradient elution with acetonitrile/water containing 0.1% ammoniumhydroxide, at flow rate of 60 mL/min) to give the desired product aswhite solid (25 mg, 19%). LCMS calc. for C₁₀H₇F₂N₂OS (M+H)⁺: m/z=241.0.Found: 241.0.

Step 6. Benzyl{(3S,5R)-1-[3-({[5-amino-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-3-yl}carbamate

Benzyl [(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(101 mg, 0.297 mmol) and5-amino-2-(2,6-difluorophenyl)-1,3-thiazole-4-carbaldehyde (82.0 mg,0.341 mmol) were dissolved in toluene (1.8 mL) and a drop of acetic acidwas added. The reaction mixture was heated at 100° C. for 2 h. Thensolvent was evaporated and methanol (1.8 mL) was added. After additionof sodium tetrahydroborate (22 mg, 0.59 mmol), the reaction mixture wasstirred for 30 min. The reaction solution was diluted with methanol andpurified by prep-LCMS (XBridge C18 column, gradient elution withacetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of60 mL/min) to give the desired product as white solid (10.5 mg, 6%).LCMS calc. for C₂₉H₃₁F₂N₆O₂S (M+H)⁺: m/z=565.2. Found: 565.2.

Step 7.N-{[5-Amino-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]methyl}-4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-amine

To a solution of benzyl{(3S,5R)-1-[3-({[5-amino-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-3-yl}carbamate(10.5 mg, 0.018 mmol) in methanol (1 mL) was added 10% palladium oncarbon (10 mg). The mixture was stirred under positive pressure of H₂overnight. The reaction mixture was filtered and the filtrate waspurified with preparative LCMS (XBridge C18 column, gradient elutionwith acetonitrile/water containing 0.1% ammonium hydroxide, at flow rateof 60 mL/min) to give the desired product as white solid (4.5 mg, 40%).LCMS calc. for C₂₁H₂₅F₂N₆S (M+H)⁺: m/z=431.2. Found: 431.2.

Example 704-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-N-[(6-{2,6-difluoro-4-[(3R)-3-fluoropyrrolidin-1-yl]phenyl}-5-fluoropyridin-2-yl)methyl]pyridin-3-amine

Step 1. (3R)-1-(3,5-Difluorophenyl)-3-fluoropyrrolidine

To a vialdicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (325.4 mg, 0.4190 mmol), (3R)-3-fluoropyrrolidine hydrochloride(from Aldrich, 0.27 g, 2.2 mmol) and cesium carbonate (2.261 g, 6.939mmol) were added. The vial was sealed with a Teflon screw-cap, evacuatedand backfilled with nitrogen (this process was repeated a total of threetimes). Anhydrous tert-butyl alcohol (11.9 mL) was added, followed bythe addition of 1-bromo-3,5-difluorobenzene (190 μL, 1.6 mmol). Thereaction mixture was heated at 90° C. for 6 h. The reaction mixture wascooled to room temperature, and diluted with EtOAc, filtered through apad of diatomaceous earth (eluted with EtOAc). The filtrate wasconcentrated, and the residue was purified by flash chromatography(gradient elution with 0-30% EtOAc in hexanes) to give the desiredproduct as a yellow solid (0.27 g, 81%). LCMS calc. for C₁₀H₁₁F₃N(M+H)⁺: m/z=202.1. Found: 202.1.

Step 2.(3R)-1-[3,5-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-fluoropyrrolidine

To a solution of (3R)-1-(3,5-difluorophenyl)-3-fluoropyrrolidine (271mg, 1.35 mmol) in THF (3.6 mL) was slowly added 2.5 M n-butyllithium inhexanes (1.1 mL, 2.7 mmol) at −78° C. After stirring at −78° C. for 1 h,2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (690 μL, 3.4 mmol)was added to the reaction mixture in one portion. The reaction mixturewas allowed to warm to room temperature and stirred at room temperaturefor 1 h. The mixture was diluted with EtOAc and NaHCO₃ solution. Theorganic layer was separated and washed with brine, dried over Na₂SO₄,and concentrated. The residue was purified with flash chromatography(gradient elution with 0-30% EtOAc in hexanes) to give the desiredproduct as a light brown solid. LCMS calc. for C₁₆H₂₂BF₃NO₂ (M+H)⁺:m/z=328.2. Found: 328.2.

Step 3.4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-N-[(6-{2,6-difluoro-4-[(3R)-3-fluoropyrrolidin-1-yl]phenyl}-5-fluoropyridin-2-yl)methyl]pyridin-3-amine

A mixture of tert-butyl[(3S,5R)-1-(3-{[(6-bromo-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(Intermediate 2; 28.1 mg, 0.0568 mmol),(3R)-1-[3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-fluoropyrrolidine(29.7 mg, 0.0908 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (3.9 mg, 0.0050 mmol) and tripotassium phosphate hydrate (28.8 mg,0.125 mmol) in 1,4-dioxane (0.61 mL)/water (0.20 mL) was degassed andstirred at 80° C. for 1.5 h. The reaction mixture was diluted with DCMand washed with water. Layers were separated and the organic layer wasdried and filtered. The filtrate was concentrated. The residue wastreated with 1:1 DCM/TFA (2 mL) for 2 h. The volatile was removed underreduced pressure and the residue was dissolved in methanol and purifiedwith prep-LCMS (XBridge C18 column, gradient elution withacetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of60 mL/min) to give the desired product as a white solid (8.9 mg, 30%).LCMS calc. for C₂₇H₃₁F₄N₆ (M+H)⁺: m/z=515.3. Found: 515.3.

Example 714-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-N-({6-[2,6-difluoro-4-(3-fluoropiperidin-1-yl)phenyl]-5-fluoropyridin-2-yl}methyl)pyridin-3-amine

This compound was synthesized according to the procedures described inExample 70, using 3-fluoropiperidine hydrochloride to replace(3R)-3-fluoropyrrolidine hydrochloride in Step 1. LCMS calc. forC₂₈H₃₃F₄N₆ (M+H)⁺: m/z=529.3. Found: 529.3.

Example 721-(4-{6-[({4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)-3-methylazetidin-3-ol

Step 1. 1-(3,5-Difluorophenyl)-3-methylazetidin-3-ol

This compound was synthesized according to the procedures described inExample 70, using 3-methylazetidin-3-ol hydrochloride to replace(3R)-3-fluoropyrrolidine hydrochloride in Step 1. LCMS calc. forC₂₇H₃₂F₃N₆O (M+H)⁺: m/z=513.3. Found: 513.3.

Example 73(3R,4R,5S)-3-Amino-1-(3-{[(6-{2,6-difluoro-4-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-4-ol

Step 1: Methyl6-(2,6-difluoro-4-hydroxyphenyl)-5-fluoropyridine-2-carboxylate

A mixture of methyl 6-chloro-5-fluoropyridine-2-carboxylate (fromFrontier Scientific, Inc., 1.90 g, 10.0 mmol),(2,6-difluoro-4-hydroxyphenyl)boronic acid (2.00 g, 11.5 mmol),N,N-diisopropylethylamine (3.4 mL, 20. mmol) in 1,4-dioxane (17 mL) andwater (1.0 mL) was purged with nitrogen, followed by addition ofbis(tri-t-butylphosphine)palladium (0.51 g, 1.0 mmol). The reactionmixture was degassed and re-charged with nitrogen for three cycles, andthen heated at 120° C. with stirring for 2 h. The reaction mixture wasallowed to cool to room temperature and concentrated under reducedpressure. The residue was purified by flash chromatography on a silicagel column with EtOAc in hexanes (gradient: 0-50%) to afford the desiredproduct (1.34 g, 47%). LCMS calc. for C₁₃H₉F₃NO₃ (M+H)⁺: 284.1. Found:284.0.

Step 2: Methyl6-{2,6-difluoro-4-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-5-fluoropyridine-2-carboxylate

To a mixture of methyl6-(2,6-difluoro-4-hydroxyphenyl)-5-fluoropyridine-2-carboxylate (283 mg,1.00 mmol) and (3S)-tetrahydrofuran-3-ol (88.1 mg, 1.00 mmol) in THF(2.0 mL) was added a solution of triphenylphosphine (524 mg, 2.00 mmol)in THF (1.0 mL), and solution of diethyl azodicarboxylate (315 μL, 2.00mmol) in THF (1.0 mL). The mixture was stirred at room temperature for 2h. The volatiles were removed under reduced pressure. The residue waspurified by flash chromatography on a silica gel column with EtOAc inhexanes (gradient: 0-60%) to afford the desired product (0.34 g, 96%).LCMS calc. for C₁₇H₁₅F₃NO₄(M+H)⁺: 354.1. Found: 354.1.

Step 3:6-{2,6-Difluoro-4-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-5-fluoropyridine-2-carboxylicacid

To a solution of methyl6-{2,6-difluoro-4-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-5-fluoropyridine-2-carboxylate(0.353 g, 1.00 mmol) in tetrahydrofuran (1.0 mL) and methanol (1.0 mL)was added lithium hydroxide monohydrate (0.0839 g, 2.00 mmol) in water(1 mL). The mixture was stirred at room temperature for 1 h., and thenneutralized with 1.0 N HCl aqueous solution (2.0 mL). The mixture wasextracted with EtOAc. The combined organic layers were dried overNa₂SO₄, filtered and concentrated under reduced pressure to afford thedesired product which was directly used in the next step reactionwithout further purification. LCMS calc. for C₁₆H₁₃F₃NO₄ (M+H)⁺: 340.1.Found: 340.1.

Step 4:(6-{2,6-Difluoro-4-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-5-fluoropyridin-2-yl)methano

To a mixture of6-{2,6-difluoro-4-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-5-fluoropyridine-2-carboxylicacid (0.319 g, 0.940 mmol) and triethylamine (151 μL, 1.08 mmol) intetrahydrofuran (5 mL) cooled in an ice bath was added isobutylchloroformate (140 uL, 1.08 mmol). The mixture was stirred for 30 min.and then sodium tetrahydroborate (76 mg, 2.0 mmol) in water (0.5 mL, 30mmol) was added dropwise. The mixture was stirred for 1 h, quenched withaq. sat. NaHCO₃ solution, and extracted with EtOAc. The combined organiclayers were washed with brine, dried over MgSO₄, filtered andconcentrated to give the title compound of Step 4, which was directlyused in the next step reaction without further purification. LCMS calc.for C₁₆H₁₅F₃NO₃ (M+H)⁺: 326.1. Found: 326.1.

Step 5:6-{2,6-Difluoro-4-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-5-fluoropyridine-2-carbaldehyde

To a mixture of(6-{2,6-difluoro-4-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-5-fluoropyridin-2-yl)methanol(the crude product from previous step) in DCM (8 mL) was addedDess-Martin periodinane (0.439 g, 1.03 mmol). The reaction mixture wasstirred at room temperature overnight. NaHCO₃ solution (7.5%, 2 mL) andNa₂S₂O₃ solution (2 mL) was added and the resulting reaction mixture wasstirred for 30 min. The product was extracted with DCM, dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by flash chromatography on a silica gel column with EtOAcin hexanes (gradient: 0-50%) to afford the desired product (0.23 g, 76%in 2 step2). LCMS calc. for C₁₆H₁₃F₃NO₃ (M+H)⁺: 324.1. Found: 324.2.

Step 6:(3R,4R,5S)-3-Amino-1-(3-{[(6-{2,6-difluoro-4-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-4-ol

tert-Butyl((3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(Prepared in Intermediate 1, Step 11; 20. mg, 0.046 mmol) and6-{2,6-difluoro-4-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-5-fluoropyridine-2-carbaldehyde(16 mg, 0.050 mmol) were dissolved in toluene (2.0 mL) and AcOH (3 uL)was added. The mixture was heated at 100° C. for 2 h. The solvent wasevaporated and methanol (2.0 mL) was added. After addition of sodiumtetrahydroborate (4.3 mg, 0.11 mmol), the resulting mixture was stirredfor 30 min. To the reaction mixture was added 4 N HCl in dioxane (1.0mL), and stirring was continued at room temperature for 1 h. The mixturewas diluted with methanol, and purified by RP-HPLC (XBridge C18 column,gradient elution with acetonitrile/water containing 0.05% TFA, at flowrate of 60 mL/min) to afford the desired product as a TFA salt. LCMScalc. for C₂₇H₃₁F₃N₅O₃(M+H)⁺:530.2. Found: 530.3.

Example 744-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-N-[(6-{2,6-difluoro-4-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-5-fluoropyridin-2-yl)methyl]pyridin-3-amine

This compound was prepared as a TFA salt by using procedures analogousto those described for the synthesis of Example 73, Step 6, startingfrom tert-butyl[(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(Prepared in Intermediate 2, Step 6) and6-{2,6-difluoro-4-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-5-fluoropyridine-2-carbaldehyde(Prepared in Example 73, Step 5). LCMS calc. for C₂₇H₃₁F₃N₅O₂(M+H)⁺:514.2. Found: 514.2.

Example 75(3R,4R,5S)-3-Amino-1-(3-{[(6-{2,6-difluoro-4-[(3S)-tetrahydrofuran-3-yloxy]phenyl}-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-4-ol

Step 1:6-{2,6-Difluoro-4-[(3S)-tetrahydrofuran-3-yloxy]phenyl}-5-fluoropyridine-2-carbaldehyde

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 73, Step 1 to 5, using(3R)-tetrahydrofuran-3-ol instead of (3S)-tetrahydrofuran-3-ol. LCMScalc. for C₁₆H₁₃F₃NO₃ (M+H)⁺: 324.1. Found: 324.1.

Step 2:(3R,4R,5S)-3-Amino-1-(3-{[(6-{2,6-difluoro-4-[(3S)-tetrahydrofuran-3-yloxy]phenyl}-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-4-ol

This compound was prepared as a TFA salt by using procedures analogousto those described for the synthesis of Example 73, Step 6 starting fromtert-butyl((3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(Prepared in Intermediate 1, Step 11) and6-{2,6-difluoro-4-[(3S)-tetrahydrofuran-3-yloxy]phenyl}-5-fluoropyridine-2-carbaldehyde.LCMS calc. for C₂₇H₃₁F₃N₅O₃(M+H)⁺: 530.2. Found: 530.2.

Example 764-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-N-[(6-{2,6-difluoro-4-[(3S)-tetrahydrofuran-3-yloxy]phenyl}-5-fluoropyridin-2-yl)methyl]pyridin-3-amine

This compound was prepared as a TFA salt by using procedures analogousto those described for the synthesis of Example 73, Step 6 starting fromtert-butyl[(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(Prepared in Intermediate 2, Step 6) and6-{2,6-difluoro-4-[(3S)-tetrahydrofuran-3-yloxy]phenyl}-5-fluoropyridine-2-carbaldehyde(Prepared in Example 75, Step 1). LCMS calc. for C₂₇H₃₁F₃N₅O₂(M+H)⁺:514.2. Found: 514.2.

Example 77(3R,4R,5S)-3-Amino-1-{3-[({6-[2,6-difluoro-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol

Step 1:6-[2,6-difluoro-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]-5-fluoropyridine-2-carbaldehyde

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 73, Step 1 to 5, usingtetrahydropyran-4-ol (from Aldrich) instead of(3S)-tetrahydrofuran-3-ol. LCMS calc. for C₁₇H₁₅F₃NO₃ (M+H)⁺: 338.1.Found: 338.1.

Step 2:(3R,4R,5S)-3-amino-1-{3-[({6-[2,6-difluoro-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol

This compound was prepared as a TFA salt by using procedures analogousto those described for the synthesis of Example 73, Step 6 starting fromtert-butyl((3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(Prepared in Intermediate 1, Step 11) and6-[2,6-difluoro-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]-5-fluoropyridine-2-carbaldehyde.LCMS calc. for C₂₈H₃₃F₃N₅O₃(M+H)⁺: 544.3. Found: 544.2.

Example 784-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-N-({6-[2,6-difluoro-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]-5-fluoropyridin-2-yl}methyl)pyridin-3-amine

This compound was prepared as a TFA salt by using procedures analogousto those described for the synthesis of Example 73, Step 6 starting fromtert-butyl[(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(Prepared in Intermediate 2, Step 6) and6-[2,6-difluoro-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]-5-fluoropyridine-2-carbaldehyde(Prepared in Example 77, Step 1). LCMS calc. for C₂₈H₃₃F₃N₅O₂(M+H)⁺:528.3. Found: 528.2.

Example 794-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-N-[(6-{2,6-difluoro-4-[(1-methylpiperidin-4-yl)oxy]phenyl}-5-fluoropyridin-2-yl)methyl]pyridin-3-amine

Step 1:6-{2,6-Difluoro-4-[(1-methylpiperidin-4-yl)oxy]phenyl}-5-fluoropyridine-2-carbaldehyde

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 73, Steps 1 to 5, using1-methylpiperidin-4-ol (from Aldrich) instead of(3S)-tetrahydrofuran-3-ol. LCMS calc. for C₁₈H₁₈F₃N₂O₂(M+H)⁺: 351.1.Found: 351.1.

Step 2:4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-N-[(6-{2,6-difluoro-4-[(1-methylpiperidin-4-yl)oxy]phenyl}-5-fluoropyridin-2-yl)methyl]pyridin-3-amine

This compound was prepared as a TFA salt by using procedures analogousto those described for the synthesis of Example 73, Step 6 starting fromtert-butyl((3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(Prepared in Intermediate 1, Step 11) and6-{2,6-difluoro-4-[(1-methylpiperidin-4-yl)oxy]phenyl}-5-fluoropyridine-2-carbaldehyde.LCMS calc. for C₂₉H₃₆F₃N₆O (M+H)⁺: 541.3. Found: 541.3.

Example 80(3R,4R,5S)-3-Amino-1-(3-{[(6-{4-[(3,3-difluorocyclobutyl)oxy]-2,6-difluorophenyl}-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-4-ol

Step 1:6-{4-[(3,3-Difluorocyclobutyl)oxy]-2,6-difluorophenyl}-5-fluoropyridine-2-carbaldehyde

This compound was prepared according to procedures analogous to thosedescribed for the synthesis of Example 73, Steps 1 to 5, using3,3-difluorocyclobutanol (from Advanced Chemblocks) instead of(3S)-tetrahydrofuran-3-ol. LCMS calc. for C₁₆H₁₁F₅NO₂ (M+H)⁺: 344.1.Found: 344.0.

Step 2:(3R,4R,5S)-3-Amino-1-(3-{[(6-{4-[(3,3-difluorocyclobutyl)oxy]-2,6-difluorophenyl}-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-4-ol

This compound was prepared as a TFA salt by using procedures analogousto those described for the synthesis of Example 73, Step 6 starting fromtert-butyl[(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(Prepared in Intermediate 2, Step 6) and6-{4-[(3,3-difluorocyclobutyl)oxy]-2,6-difluorophenyl}-5-fluoropyridine-2-carbaldehyde.LCMS calc. for C₂₇H₂₉F₅N₅O₂ (M+H)⁺: 550.2. Found: 550.2.

Example 814-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-N-[(6-{4-[(3,3-difluorocyclobutyl)oxy]-2,6-difluorophenyl}-5-fluoropyridin-2-yl)methyl]pyridin-3-amine

This compound was prepared as a TFA salt by using procedures analogousto those described for the synthesis of Example 73, Step 6 starting fromtert-butyl((3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(Prepared in Intermediate 1, Step 11) and6-{4-[(3,3-difluorocyclobutyl)oxy]-2,6-difluorophenyl}-5-fluoropyridine-2-carbaldehyde(Prepared in Example 80, Step 1). LCMS calc. for C₂₇H₂₉F₅N₅O (M+H)⁺:534.2. Found: 534.2.

Example 82(3R,4R,5S)-3-Amino-1-[3-({[6-(2,6-difluoro-4-methoxyphenyl)-5-fluoropyridin-2-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-4-ol

A mixture of (2,6-difluoro-4-methoxyphenyl)boronic acid (from Aldrich,9.40 mg, 0.0500 mmol), tert-butyl((3R,4R,5S)-1-(3-{[(6-bromo-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate (Intermediate 1, 31.2 mg,0.0500 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (3.93 mg, 0.00500 mmol) and cesium carbonate (32.6 mg, 0.100 mmol)was evacuated and recharged with nitrogen. Then 1,4-dioxane (0.25 mL)and water (0.15 mL) was added, and re-evacuated and recharged with N₂three times. The reaction mixture was stirred at 70° C. for 1 h. Aftercooling, the mixture was diluted with EtOAc, washed with water andbrine. The organic layer was dried over MgSO₄, filtered and concentratedunder reduced pressure. The residue was treated with 4 N HCl in dioxane(1.0 mL) and methanol (0.5 mL). The mixture was stirred at roomtemperature for 1 h. diluted with methanol, and purified by RP-HPLC(XBridge C18 column, gradient elution with acetonitrile/water containing0.05% TFA, at flow rate of 60 mL/min) to afford the desired product asTFA salt. LCMS calc. for C₂₄H₂₇F₃N₅O₂(M+H)⁺: 474.2. Found: 474.2.

Example 834-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-N-{[6-(2,6-difluoro-4-methoxyphenyl)-5-fluoropyridin-2-yl]methyl}pyridin-3-amine

This compound was prepared as a TFA salt by using procedures analogousto those described for the synthesis of Example 82, Step 4 starting fromtert-butyl[(3S,5R)-1-(3-{[(6-bromo-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(Intermediate 2) and (2,6-difluoro-4-methoxyphenyl)boronic acid. LCMScalc. for C₂₄H₂₇F₃N₅O (M+H)⁺: 458.2. Found: 458.2.

Example 844-{6-[({4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3-fluorobenzonitrile

This compound was prepared as a TFA salt by using procedures analogousto those described for the synthesis of Example 82, Step 4 starting fromtert-butyl[(3S,5R)-1-(3-{[(6-bromo-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(Intermediate 2) and (4-cyano-2-fluorophenyl)boronic acid (fromCombi-Blocks). LCMS calc. for C₂₄H₂₅F₂N₆ (M+H)⁺: 435.2. Found: 435.2.

Example 854-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-N-{[6-(1-benzothien-5-yl)-5-fluoropyridin-2-yl]methyl}pyridin-3-amine

This compound was prepared as a TFA salt by using procedures analogousto those described for the synthesis of Example 82, Step 4 starting fromtert-butyl[(3S,5R)-1-(3-{[(6-bromo-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(Intermediate 2) and2-(1-benzothien-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (fromMaybridge). LCMS calc. for C₂₅H₂₇FN₅S (M+H)⁺: 448.2. Found: 448.2.

Example 866-{6-[({4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-1,3-dihydro-2H-indol-2-one

This compound was prepared as a TFA salt by using procedures analogousto those described for the synthesis of Example 82, Step 4 starting fromtert-butyl[(3S,5R)-1-(3-{[(6-bromo-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(Intermediate 2) and (2-oxo-2,3-dihydro-1H-indol-6-yl)boronic acid (fromCombi-Blocks). LCMS calc. for C₂₅H₂₈FN₆O (M+H)⁺: 447.2. Found: 447.2.

Example 87(7S)-4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-oland(7R)-4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol

Step 1: 6, 7-Dihydro-5H-cyclopenta[b]pyridine 1-oxide

mCPBA (10.0 g, 44.6 mmol) was added slowly to a mixture of6,7-dihydro-5H-cyclopenta[b]pyridine (from Aldrich, 5.0 g, 42 mmol) inDCM (50 mL). The reaction mixture was stirred at room temperature for 2h. The solution was then washed with aqueous Na₂S₂₀₃ (50 mL) and 1 MNaOH (50 mL). The aqueous layer was extracted with DCM (5×70 mL). Thecombined organic layers were dried, filtered and concentrated underreduced pressure to give the sub-title compound (4.5 g, 79%). LCMS calc.for C₈H₁₀NO (M+H)⁺: m/z=136.1. Found: 136.2.

Step 2: 4-Chloro-6,7-dihydro-5H-cyclopenta[b]pyridine

6,7-Dihydro-5H-cyclopenta[b]pyridine 1-oxide (2.5 g, 18 mmol) was mixedwith POCl₃ (20 mL). The reaction mixture was stirred at 120° C. for 3 h.The excess POCl₃ was removed under reduced pressure. The residue wasdissolved in EtOAc (80 mL) and neutralized with aq. Na₂CO₃. Afterfiltration, the aqueous layer was extracted with EtOAc twice. Thecombined organic layers were dried, filtered and concentrated underreduced pressure to give the sub-title compound (2.6 g, 93%). LCMS calc.for C₈H₉ClN (M+H)⁺: m/z=154.0. Found: 154.3.

Step 3: 4-Methoxy-6,7-dihydro-5H-cyclopenta[b]pyridine

A mixture of 4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine (2.8 g, 18mmol), MeOH (20 mL) and sodium methoxide (3.0 g, 56 mmol) was sealed ina pressurized flask and heated at 110° C. for 18 h. The mixture wasdiluted with EtOAc and neutralized with HCl to pH=1. The organic solventwas removed under reduced pressure. The resulting mixture was washedwith ether twice, and then neutralized with Na₂CO₃ solution. The aqueouslayer was extracted twice with EtOAc. The combined organic layers weredried, filtered and concentrated under reduced pressure to give thesub-title compound (1.20 g, 44%). LCMS calc. for C₉H₁₂NO (M+H)⁺:m/z=150.1. Found: 150.2.

Step 4: 4-Methoxy-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine

4-Methoxy-6,7-dihydro-5H-cyclopenta[b]pyridine (2.90 g, 19.4 mmol) wasmixed with concentrated sulfuric acid (17.0 g, 173 mmol) at 0° C., thena mixture of potassium nitrate (5.3 g, 52 mmol) in another portion ofconcentrated sulfuric acid (26.5 g, 270 mmol) was added slowly. Thereaction mixture was heated at 80° C. for 4 h. The crude mixture wasslowly poured onto crushed ice (50 g), and neutralized carefully with50% aqueous NaOH to pH 8-9. The resulting mixture was extracted withEtOAc five times. The combined organic extracts were dried andconcentrated under reduced pressure to give the crude sub-title compoundas brown gum (1.56 g, 41%), which was used without further purification.LCMS calc. for C₉H₁₁N₂O₃(M+H)⁺: m/z=195.1. Found: 195.2.

Step 5: 3-Nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-ol

A mixture of 4-methoxy-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine(1.535 g, 7.905 mmol) in acetic acid (2.6 mL) was treated 48% aqueousHBr (2.6 mL, 23 mmol). The flask containing the reaction mixture wassealed and heated at 130° C. for 40 min., then allowed to cool. Theresulting reaction mixture was concentrated under reduced pressure, theresidue was neutralized to pH=7-8 using 50% NaOH with cooling. Afterfurther concentrating, the residue was diluted with MeOH and THF, dried,filtered and concentrated to give the crude sub-title compound as lightbrown powder, which was used without further purification. LCMS calc.for C₈H₉N₂O₃ (M+H)⁺: m/z=181.1. Found: 181.2.

Step 6: 4-Chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine

A solution of 3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-ol (1.424 g,7.904 mmol) in POCl₃ (11.0 mL) was heated at 110° C. in a sealed flaskunder N₂ for 2 h. The crude mixture was cooled to room temperature, andconcentrated under reduced pressure. The residue was carefully quenchedwith ice, and neutralized with 50% NaOH to pH 7. The resulting mixturewas extracted with EtOAc three times. The combined organic layers weredried, filtered and concentrated under reduced pressure to give thecrude sub-title compound as a brown solid (0.82 g, 52%), which was usedwithout further purification. LCMS calc. for C₈H₈N₂O₂(M+H)⁺: m/z=199.0.Found: 199.2.

Step 7: tert-Butyl[(3S,5R)-5-methyl-1-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate

A mixture of 4-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine (19.4mg, 0.10 mmol), tert-butyl [(3S,5R)-5-methylpiperidin-3-yl]carbamate(Prepared in Intermediate 2, Step 4; 22.0 mg, 0.10 mmol) andtriethylamine (40.9 μL, 0.29 mmol) in isopropyl alcohol (0.224 mL) wasstirred at 100° C. for 40 min. The reaction mixture was concentratedunder vacuum and the residue was purified by silica gel columnchromatography using CombiFlash®(gradient elution with 0 to 50% EtOAc inhexanes) to give the sub-title compound as pale yellow powder (36.8 mg,100%). LCMS calc. for C₁₉H₂₉N₄O₄ (M+H)⁺: m/z=377.1. Found: 377.1.

Step 8: tert-Butyl[(3S,5R)-5-methyl-1-(3-nitro-1-oxido-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate

To a solution of tert-butyl[(3S,5R)-5-methyl-1-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate(32.3 mg, 0.086 mmol) in DCM (0.50 mL) at 0° C. was added mCPBA (25.0mg, 0.112 mmol). The reaction mixture was stirred at room temperaturefor 1 h. The mixture was treated with Na₂S₂O₃ solution, followed by theaddition of 1N NaOH, and stirred for 30 min. at room temperature. Theorganic layer was separated, dried, filtered and concentrated undervacuum to give the crude N-oxide product. The crude product was purifiedby preparative LCMS (XBridge™ preparative C18 5 μm OBD™ column, 30×10mm, 60 mL/min., gradient elution with MeCN and water with 0.1% NH₄OH) toafford the sub-title compound (20 mg, 40%). LCMS calc. for C₁₉H₂₉N₄O₅(M+H)⁺: m/z=393.2. Found: 393.1.

Step 9:4-{(3S,5R)-3-[(tert-Butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate

Acetic anhydride (15.6 mg, 0.153 mmol) was added to the N-oxidetert-butyl[(3S,5R)-5-methyl-1-(3-nitro-1-oxido-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate(10.0 mg, 0.026 mmol) in a sealed tube. The reaction mixture was heatedat 90° C. for 30 min. and the solution was then concentrated underreduced pressure. The residue was then dissolved in DCM, then pouredinto ice cold Na₂CO₃ solution. The aqueous layer was extracted with DCMtwice. The combined organic layers were dried, filtered and concentratedunder reduced pressure to give the sub-title compound as off-whitepowder (11.2 mg, 95%). LCMS calc. for C₂₁H₃₁N₄O₆ (M+H)⁺: m/z=435.2.Found: 435.1.

Step 10:3-Amino-4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate

A mixture of4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (11.2 mg, 0.026 mmol), acetic acid (73.3 μL) and iron powder(14.4 mg, 0.26 mmol) was stirred at room temperature for 3 h. Thereaction mixture was diluted with EtOAc, filtered and washed with moreEtOAc. The filtrate was concentrated under vacuum, and the residue wasdiluted with EtOAc and neutralized with Na₂CO₃ solution. The mixture wasstirred at room temperature for 30 min. The organic layer was separated,dried over Na₂SO₄, filtered and concentrated under vacuum to give thesub-title compound as a yellow solid (10.0 mg, 96%). LCMS calc. forC₂₁H₃₃N₄O₄ (M+H)⁺: m/z=405.2. Found: 405.1.

Step 11:4-{(3S,5R)-3-[(tert-Butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate

3-Amino-4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (18.8 mg, 0.046 mmol) and6-(2,6-difluorophenyl)-5-fluoropyridine-2-carbaldehyde (Prepared inExample 66, Step 4; 10.0 mg, 0.042 mmol) were dissolved in toluene (0.9mL) and AcOH (catalytic amount) was added. The reaction mixture washeated at 120 Celsius for 3 h. The solvent was evaporated under vacuumand methanol (0.94 mL) was added, followed by the addition of sodiumtetrahydroborate (4.0 mg, 0.10 mmol). The reaction mixture was stirredat room temperature for 30 min. The crude product was purified by prepLCMS (XBridge™ PrepC18 5 μm OBD™ column, 30×10 mm, 60 mL/min, gradientelution with MeCN and water with NH₄OH) to give the desired product (8.0mg). LCMS calc. for C₃₃H₃₉F₃N₅O₄(M+H)⁺: m/z=626.3. Found: 626.3.

Step 12:(7S)-4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-oland(7R)-4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol

4-{(3S,5R)-3-[(tert-Butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylacetate (8.0 mg, 0.013 mmol) was mixed with methanol (0.03 mL),tetrahydrofuran (0.2 mL) and 1.0 M sodium hydroxide in water (0.064 mL,0.064 mmol). The reaction mixture was stirred at room temperature for 20min. The organic solvents and trace of water were removed under vacuumto give the crude intermediate, which was treated with 4.0 M hydrogenchloride in dioxane (0.16 mL, 0.64 mmol). The mixture was stirred atroom temperature for 10 min. After concentration, the residue wasdiluted with NH₄OH and MeOH, filtered and purified by prep LCMS(XBridge™ PrepC18 5 μm OBD™ column, 30×10 mm, 60 mL/min, gradientelution with MeCN and water with NH₄OH) to give two diastereomers(Diastereoisomers 1 and 2) which were tentatively assigned as(7S)-4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-oland(7R)-4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol.Analytical data were obtained for the second diastereomer eluted (1.2mg). LCMS calc. for C₂₆H₂₉F₃N₅O (M+H)⁺: m/z=484.2. Found: 484.2.

Example 88(3R,4R,5S)-3-Amino-1-[5-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}amino)-2,3-dihydrofuro[2,3-b]pyridin-4-yl]-5-methylpiperidin-4-ol

Step 1. 2-(2-Fluoro-4-iodopyridin-3-yl)ethanol

A solution of 2.0 M lithium diisopropylamide in heptane/THF/ethylbenzene(8.10 mL, 16.2 mmol) was added to a solution of 2-fluoro-4-iodopyridine(Ark Pharm, 2.989 g, 13.40 mmol) in THF (50 mL) at −78° C., then themixture was stirred at −78° C. for 90 min. With the temperaturemaintained at −78° C., a solution of 1,3,2-dioxathiolane 2,2-dioxide(2.206 g, 17.77 mmol) in THF (30 mL) was added slowly over a period of20 min., the solution was stirred at −78° C. for a further 20 min., thenallowed to warm to room temperature and stirred for 2 h at thattemperature. The mixture was then cooled to 0° C., and 12.0 M aqueousHCl (5.0 mL, 60. mmol) was added. The reaction mixture was allowed towarm to room temperature and stirred at that temperature for 3 h.Saturated aqueous NaHCO₃ (250 mL) was added, then the reaction mixturewas extracted with EtOAc (3×150 mL). The combined extracts were washedwith brine (250 mL), dried over Na₂SO₄ and concentrated under reducedpressure. The residue was purified by chromatography on silica gel(gradient elution with 0-100% EtOAc in hexanes) to give the sub-titlecompound as a white solid (3.13 g, 87%). LCMS calc. for C₇H₈FINO (M+H)⁺:m/z=268.0. found 268.0.

Step 2. 4-Iodo-2,3-dihydrofuro[2,3-b]pyridine

Potassium phosphate (10.0 g, 47.1 mmol) was added to a solution of2-(2-fluoro-4-iodopyridin-3-yl)ethanol (3.13 g, 11.7 mmol) in1,4-dioxane (100 mL). The mixture was heated under reflux for 36 h. Thereaction mixture was filtered, and the filter cake was washed withEtOAc. The combined filtrates were concentrated under reduced pressure.The residue was dissolved in DCM (100 mL), washed with brine (2×100 mL),dried over Na₂SO₄ and concentrated under reduced pressure. The resultingresidue (2.55 g) containing the sub-title compound was used in the nextstep directly without further purification. LCMS calc. for C₇H₇INO(M+H)⁺: m/z=247.9. found 248.0.

Step 3. 4-Iodo-5-nitro-2,3-dihydrofuro[2,3-b]pyridine

A solution of fuming nitric acid (15.0 mL, 358 mmol) in concentratedsulfuric acid (15.0 mL, 281 mmol) was added slowly over a period of 15min. to a stirred solution of 4-iodo-2,3-dihydrofuro[2,3-b]pyridine(2.237 g, 9.055 mmol) in sulfuric acid (10.0 mL, 188 mmol) at −10° C.The reaction mixture was allowed to warm to room temperature, andstirred for a further 16 h. The reaction mixture was quenched by pouringonto crushed ice and was then extracted with EtOAc (6×100 mL). Theorganic extracts were combined and washed with saturated aqueous NaHCO₃(2×300 mL) and brine (300 mL), then dried over Na₂SO₄, and concentratedunder reduced pressure. The residue was purified by chromatography onsilica gel (gradient elution with 0-100% EtOAc in hexanes) to give thesub-title compound as a pale yellow solid (2.43 g, 92%). LCMS calc. forC₇H₆IN₂O₃(M+H)⁺: m/z=292.9. found 293.0.

Step 4. tert-Butyl[(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methyl-1-(5-nitro-2,3-dihydrofuro[2,3-b]pyridin-4-yl)piperidin-3-yl]carbamate

To a mixture of 4-iodo-5-nitro-2,3-dihydrofuro[2,3-b]pyridine (110.4 mg,0.3780 mmol) and tert-butyl((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(Prepared in Intermediate 1, Step 9; 100.0 mg, 0.2902 mmol) was addedEtOH (2.0 mL) followed by the addition of DIPEA (163.8 mg, 1.267 mmol).The reaction mixture was heated at 100° C. for 15 h, and thenconcentrated under reduced pressure. The residue was purified bychromatography on silica gel (gradient elution with 0-50% EtOAc inhexanes) to afford the sub-title compound as a yellow solid (118.2 mg,80%). LCMS calc. for C₂₄H₄₁N₄O₆Si (M+H)⁺: m/z=509.3. found 509.3.

Step 5. tert-Butyl((3R,4R,5S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate

To a mixture of tert-butyl[(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methyl-1-(5-nitro-2,3-dihydrofuro[2,3-b]pyridin-4-yl)piperidin-3-yl]carbamate(73.4 mg, 0.144 mmol), iron powder (89.0 mg, 1.59 mmol), and ammoniumchloride (151.4 mg, 2.830 mmol) was added EtOH (2.0 mL), followed by theaddition of water (0.50 mL, 28 mmol). The reaction mixture was stirredat 80° C. for 1 h. The reaction mixture was filtered through a pad ofdiatomaceous earth. The diatomaceous earth pad was eluted with a 10%aqueous solution of K₃PO₄ (20 mL), and EtOAc (20 mL). The organic layerswere washed with brine (20 mL), dried over Na₂SO₄, and concentrated togive the crude sub-title compound (67.8 mg). The crude product was useddirectly in the next step without further purification. LCMS calc. forC₂₄H₄₃N₄O₄Si (M+H)⁺: m/z=479.3. found 479.3.

Step 6: tert-Butyl{(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-[5-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}amino)-2,3-dihydrofuro[2,3-b]pyridin-4-yl]-5-methylpiperidin-3-yl}carbamate

tert-Butyl((3R,4R,5S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(31.1 mg, 0.065 mmol) and6-(2,6-difluorophenyl)-5-fluoropyridine-2-carbaldehyde (Prepared inExample 66, Step 4; 14.0 mg, 0.06 mmol) were dissolved in toluene (0.60mL) and AcOH (catalytic amount) was added. The reaction mixture washeated at 125° C. for 3 h. The solvent was evaporated under vacuum andmethanol (0.60 mL) was added, followed by the addition of sodiumtetrahydroborate (11 mg, 0.30 mmol) at 0° C. The reaction mixture wasstirred at room temperature for 30 min. After formation of the desiredproduct, as determined by LCMS, the reaction mixture was concentratedand the residue was used directly in the next step. LCMS calc. forC₃₆H₄₉F₃N₅O₄Si (M+H)⁺: m/z=700.3. Found: 700.3.

Step 7:(3R,4R,5S)-3-Amino-1-[5-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}amino)-2,3-dihydrofuro[2,3-b]pyridin-4-yl]-5-methylpiperidin-4-ol

tert-Butyl{(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-[5-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}amino)-2,3-dihydrofuro[2,3-b]pyridin-4-yl]-5-methylpiperidin-3-yl}carbamate(9.8 mg, 0.014 mmol) was mixed with methanol (0.11 mL) and 4.0 Mhydrogen chloride in dioxane (0.17 mL, 0.70 mmol). The reaction mixturewas stirred at room temperature for 20 min. After concentrated underreduced pressure, the residue was dissolved in NH₄OH and MeOH, filteredand purified by prep LCMS (XBridge™ PrepC18 5 μm OBD™ column, 30×10 mm,60 mL/min, gradient elution with MeCN and water with NH₄OH) to give thedesired product as white powders (4.5 mg, 66%). LCMS calc. forC₂₅H₂₇F₃N₅O₂ (M+H)⁺: m/z=486.2. Found: 486.2.

Example 894-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-N-{[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}-6,7-dihydro-5H-cyclopenta[b]pyridin-3-amine

Step 1. tert-Butyl[(3S,5R)-1-(3-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate

A mixture of tert-Butyl[(3S,5R)-5-methyl-1-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate(from Example 87 step 7, 0.435 g, 1.16 mmol), acetic acid (6.5 mL) andiron powder (1.32 g, 23.6 mmol) were stirred at rt for 3 h. The reactionmixture was diluted with EtOAc, filtered through a celite pad. Thefiltrate was concentrated under vacuum, diluted with dichloromethane andneutralized with NaOH (2 N). The organic layer was separated, dried overK₂CO₃, filtered and concentrated under vacuum to give the desiredproduct as light brown powders (365 mg, 91%). LCMS calcd for C₁₉H₃₁N₄O₂(M+H)⁺: m/z=347.2. Found: 347.1.

Step 2: tert-Butyl{(3S,5R)-1-[3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]-5-methylpiperidin-3-yl}carbamate

tert-Butyl[(3S,5R)-1-(3-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(22.5 mg, 0.065 mmol) and6-(2,6-difluorophenyl)-5-fluoropyridine-2-carbaldehyde (Prepared inExample 66, Step 4; 14.0 mg, 0.059 mmol) were dissolved in toluene (0.60mL) and AcOH (catalytic amount) was added. The reaction mixture washeated at 125° C. for 3 h. The solvent was evaporated and methanol (0.6mL) was added, followed by the addition of sodium tetrahydroborate (11mg, 0.3 mmol) at 0° C. The reaction mixture was stirred at roomtemperature for 30 min and then concentrated under reduced pressure anddirectly used in the next step. LCMS calc. for C₃₁H₃₇F₃N₅O₂(M+H)⁺:m/z=568.3. Found: 568.3.

Step 3:4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-N-{[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}-6,7-dihydro-5H-cyclopenta[b]pyridin-3-amine

tert-Butyl{(3S,5R)-1-[3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]-5-methylpiperidin-3-yl}carbamate(11.0 mg, 0.019 mmol) was mixed with methanol (0.16 mL) and 4.0 Mhydrogen chloride in dioxane (0.24 mL, 0.97 mmol). The reaction mixturewas stirred at room temperature for 20 min. After concentrated underreduced pressure, the residue was dissolved in NH₄OH and MeOH, filteredand purified by prep LCMS (XBridge™ PrepC18 5 μm OBD™ column, 30×10 mm,60 mL/min, gradient elution with MeCN and water with NH₄OH) to give thedesired product as white powder (3.4 mg, 38%). LCMS calc. for C₂₆H₂₉F₃N₅(M+H)⁺: m/z=468.2. Found: 468.2.

Example 904-[(3R,4R)-3-Amino-4-fluoropiperidin-1-yl]-N-{[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}pyridin-3-amine

Step 1: tert-Butyl[(3R,4R)-4-fluoro-1-(3-nitropyridin-4-yl)piperidin-3-yl]carbamate

A mixture of 4-chloro-3-nitropyridine (191 mg, 1.20 mmol), tert-butyl[(3R,4R)-4-fluoropiperidin-3-yl]carbamate (from Synnovator, 250 mg, 1.15mmol) and triethylamine (0.48 mL, 3.4 mmol) in isopropyl alcohol (1.23mL) was stirred at 100° C. for 60 min. The reaction mixture was purifiedby Biotage column to give the pure product as pale yellow powder (452mg, 100% yield). LCMS calc. for C₁₅H₂₂FN₄O₄(M+H)⁺: m/z=341.2. Found:341.3.

Step 2: tert-Butyl[(3R,4R)-1-(3-aminopyridin-4-yl)-4-fluoropiperidin-3-yl]carbamate

tert-Butyl[(3R,4R)-4-fluoro-1-(3-nitropyridin-4-yl)piperidin-3-yl]carbamate (0.39g, 1.14 mmol) was dissolved in methanol (8 mL). To the above solutionwas added palladium hydroxide (0.12 g) (20% palladium on carbon) undernitrogen. The system was de-gassed and recharged with hydrogen threetimes and then the reaction mixture was shaken under Parr-sharker at 45psi of H₂ for 1 h. The mixture was filtered through a pad ofdiatomaceous earth and rinsed with MeOH. The filtrate was concentratedunder reduced pressure to afford the desired product (356 mg, 100%) aslight brown powder. LCMS calc. for C₁₅H₂₄FN₄O₂(M+H)⁺: m/z=311.2. Found:311.2.

Step 3: tert-Butyl{(3R,4R)-1-[3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}amino)pyridin-4-yl]-4-fluoropiperidin-3-yl}carbamate

tert-Butyl[(3R,4R)-1-(3-aminopyridin-4-yl)-4-fluoropiperidin-3-yl]carbamate (20.2mg, 0.065 mmol) and6-(2,6-difluorophenyl)-5-fluoropyridine-2-carbaldehyde (Prepared inExample 66, Step 4; 14.0 mg, 0.059 mmol) were dissolved in toluene (0.65mL) and AcOH (catalytic amount) was added. The reaction mixture washeated at 130° C. for 3 h. The solvent was evaporated under vacuum andmethanol (0.6 mL) was added, followed by the addition of sodiumtetrahydroborate (22.3 mg, 0.59 mmol) at 0° C. The reaction mixture wasstirred at room temperature for 50 min and then concentrated undervacuum to give the desired crude product. LCMS calc. forC₂₇H₃₀F₄N₅O₂(M+H)⁺: m/z=532.2. Found: 532.2.

Step 4:4-[(3R,4R)-3-Amino-4-fluoropiperidin-1-yl]-N-{[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}pyridin-3-amine

tert-Butyl{(3R,4R)-1-[3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}amino)pyridin-4-yl]-4-fluoropiperidin-3-yl}carbamate(31.0 mg, 0.058 mmol) was mixed with methanol (0.5 mL) and 4.0 Mhydrogen chloride in dioxane (0.73 mL, 2.9 mmol). The reaction mixturewas stirred at room temperature for 30 min. After concentrated underreduced pressure, the residue was dissolved in NH₄OH and MeOH, filteredand purified by prep LCMS (XBridge™ PrepC18 5 μm OBD™ column, 30×10 mm,60 mL/min, gradient elution with MeCN and water with NH₄OH) to give thedesired product as a white powder (13.3 mg, 53%). LCMS calc. forC₂₂H₂₂F₄N₅ (M+H)⁺: m/z=432.2. Found: 432.2.

Example 914-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-N-{[7-(2,3-dihydro-1-benzofuran-6-yl)quinolin-2-yl]methyl}pyridin-3-amine

Step 1: (7-Bromoquinolin-2-yl)methanol

To a mixture of 7-bromoquinoline-2-carboxylic acid (from Aldrich, 0.80g, 3.2 mmol) and triethylamine (0.49 mL, 3.5 mmol) in tetrahydrofuran(20 mL) was slowly added isobutyl chloroformate (0.45 mL, 3.8 mmol). Thereaction mixture was stirred at room temperature for 1 h. Thepresipitate was removed by filtration. The filtrate was cooled in an icebath and a solution of sodium borohydride (1.20 g, 4.0 mmol) in water(15.0 mL) was added dropwise. The mixture was stirred for 1 h, quenchedwith NaHCO₃ (aqueous) solution, extracted with EtOAc, washed with brine,dried over MgSO₄ and concentrated to give the desired product. LCMScalc. for C₁₀H₉BrNO (M+H)⁺: m/z=238.0. Found: 238.0.

Step 2: 7-Bromoquinoline-2-carbaldehyde

A solution of (7-bromoquinolin-2-yl)methanol (0.77 g, 3.2 mmol) in DCM(10 mL) at 0° C. was added Dess-Martin periodinane (2.0 g, 4.7 mmol).The reaction mixture was stirred at room temperature overnight and thenconcentrated under vacuum. The crude residue was purified by silica gelcolumn chromatography (gradient elution with EtOAc in hexanes 0-50%) togive the desired product as a colorless solid. LCMS calc. for C₁₀H₇BrNO(M+H)⁺: m/z=236.0. Found: 235.9.

Step 3: tert-Butyl[(3S,5R)-1-(3-{[(7-bromoquinolin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate

tert-Butyl[(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(Prepared in Intermediate 2, Step 6; 0.23 g, 0.75 mmol) and7-bromoquinoline-2-carbaldehyde (0.16 g, 0.68 mmol) were dissolved intoluene (7.5 mL) and AcOH (catalytic amount) was added. The reactionmixture was heated at 130° C. for 3 h. The solvent was evaporated undervacuum and methanol (6.9 mL) was added, followed by the addition ofsodium tetrahydroborate (0.26 g, 6.82 mmol) at 0° C. The reactionmixture was stirred at room temperature for 50 min, then concentratedunder reduced pressure and purified by silica gel column chromatography(gradient elution with 0-100% EtOAc in hexanes) to give the desiredproduct as a light yellow powder. LCMS calc. for C₂₆H₃₃BrN₅O₂(M+H)⁺:m/z=526.2. Found: 526.2.

Step 4:4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-N-{[7-(2,3-dihydro-1-benzofuran-6-yl)quinolin-2-yl]methyl}pyridin-3-amine

6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1-benzofuran(from Ark Pharma, 0.018 g, 0.072 mmol), tert-butyl[(3S,5R)-1-(3-{[(7-bromoquinolin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(16.0 mg, 0.03 mmol), 1,4-dioxane (0.17 mL) and DIPEA (17.3 mg, 0.134mmol) and water (0.017 mL) were mixed together. The mixture was flushedwith nitrogen and then bis(tri-tert-butylphosphine)palladium (7.0 mg,0.01 mmol) was added. The reaction mixture was sealed and heated at 120°C. for 2 h. The reaction mixture was cooled, filtered and concentratedunder vacuum. The residue was dissolved in MeOH (1 mL), followed by theaddition of 4 N HCl in dioxane (2.0 mL) to the resultant solution. Thereaction mixture was stirred at room temperature for 2 h, and thesolvents were removed under vacuum. The residue was purified by prepLCMS (XBridge™ PrepC18 5 μm OBD™ column, 30×10 mm, 60 mL/min, gradientelution with MeCN and water with NH₄OH) to give the desired product as awhite powder. LCMS calc. for C₂₉H₃₂N₅₀ (M+H)⁺: m/z=466.3. Found: 466.3.

Example 924-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-N-[(7-imidazo[1,2-a]pyridin-7-ylquinolin-2-yl)methyl]pyridin-3-amine

7-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine(from J&W Pharma, 10.0 mg, 0.041 mmol), tert-butyl[(3S,5R)-1-(3-{[(7-bromoquinolin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(Prepared in Example 91, Step 3; 16.0 mg, 0.03 mmol), 1,4-dioxane (0.17mL) and N,N-diisopropylethylamine (17.3 mg, 0.134 mmol) and water (0.02mL) were mixed together. The reaction mixture was flushed with nitrogenand then bis(tri-t-butylphosphine)palladium (7.0 mg, 0.01 mmol) wasadded. The reaction mixture was sealed and heated at 120° C. for 2 h.The reaction mixture was filtered and concentrated under vacuum. Theresidue was dissolved in MeOH (1.0 mL), followed by the addition of 4 NHCl in dioxane (2.0 mL). The reaction mixture was stirred at roomtemperature for 1 h. The solvents were removed under vacuum. The residuewas purified by prep LCMS (XBridge™ PrepC18 5 μm OBD™ column, 30×10 mm,60 mL/min, gradient elution with MeCN and water with NH₄OH) to give thedesired product as a white powder. LCMS calc. for C₂₈H₃₀N₇ (M+H)⁺:m/z=464.3. Found: 464.3.

Example 93 (3R,4R,5S)-3-Amino-1-(3-{[(7-imidazo[1,2-a]pyridin-7-ylquinolin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-4-ol

Step 1: tert-Butyl((3R,4R,5S)-1-(3-{[(7-bromoquinolin-2-yl)methyl]amino}pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate

tert-Butyl((3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(Prepared in Intermediate 1, Step 11; 0.30 g, 0.68 mmol) and7-bromoquinoline-2-carbaldehyde (Prepared in Example 91, Step 2; 0.16 g,0.68 mmol) were dissolved in toluene (7.5 mL) and acetic acid (catalyticamount) was added. The reaction mixture was heated at 130° C. for 3 h.The solvent was evaporated and methanol (6.9 mL) was added, followed bythe addition of sodium tetrahydroborate (0.258 g, 6.8 mmol) at 0° C. Thereaction mixture was stirred at room temperature for 50 min andconcentrated under vacuum. The residue was diluted with EtOAc and NaHCO₃aqueous solution. The aqueous layer was extracted with EtOAc twice. Theorganic layers were combined, filtered and concentrated. The crudeproduct was purified by silica gel column chromatography (0-100% EtOAcin hexanes, then 0-30% MeOH in EtOAc) to give the desired product as alight yellow powder. LCMS calc. for C₃₂H₄₇BrN₅O₃Si (M+H)⁺: m/z=656.3.Found: 656.2.

Step 2:(3R,4R,5S)-3-Amino-1-(3-{[(7-imidazo[1,2-a]pyridin-7-ylquinolin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-4-ol

7-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine(10.0 mg, 0.041 mmol), tert-butyl((3R,4R,5S)-1-(3-{[(7-bromoquinolin-2-yl)methyl]amino}pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(20.0 mg, 0.030 mmol), 1,4-dioxane (0.17 mL) andN,N-diisopropylethylamine (17.3 mg, 0.13 mmol) and water (0.017 mL) weremixed together. The reaction mixture was flushed with nitrogen and thenbis(tri-tert-butylphosphine)palladium (7.0 mg, 0.01 mmol) was added. Thereaction mixture was sealed and heated at 120° C. for 2 h. The reactionmixture was concentrated under vacuum. The residue was treated with 4NHCl in dioxane (2.0 mL) at room temperature for 2 h. The solvents wereremoved under vacuum. The residue was purified by prep LCMS (XBridge™PrepC18 5 μm OBD™ column, 30×10 mm, 60 mL/min, gradient elution withMeCN and water with NH₄OH) to give the desired product as a whitepowder. LCMS calc. for C₂₈H₃₀N₇O (M+H)⁺: m/z=480.2. Found: 480.3.

Example 94(3R,4R,5S)-3-Amino-1-{3-[({6-[2,6-difluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol

Step 1: 4-(3, 5Difluorophenyl)-1-methyl-1H-pyrazole

To a degassed mixture of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(from Aldrich, 0.30 g, 1.4 mmol), 1-bromo-3,5-difluorobenzene (fromAldrich, 0.28 g, 1.4 mmol), 1,4-dioxane (3.5 mL),N,N-diisopropylethylamine (0.35 g, 2.7 mmol) and water (0.35 mL) wereadded bis(tri-t-butylphosphine)palladium (0.10 g, 0.30 mmol). Thereaction mixture was sealed in a microwave tube and heated at 120° C.for 1 h. The mixture was filtered. The filtrate was concentrated andpurified by silica gel column chromatography (eluted with EtOAc inhexanes 0-50%) to give the desired product (0.23 g, 82%). LCMS calc. forC₁₀H₉F₂N₂ (M+H)⁺: m/z=195.1. Found: 195.1.

Step 2:4-[3,5-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-methyl-1H-pyrazole

To a solution of 4-(3,5-difluorophenyl)-1-methyl-1H-pyrazole (0.23 g,1.2 mmol) in tetrahydrofuran (4 mL) at −78° C. was added 2.5 Mn-butyllithium in hexane (1.4 mL, 3.6 mmol). The reaction mixture wasstirred at −78° C. for 1 h, followed by the addition of2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.60 mL, 2.96mmol). The mixture was allowed to warm up to rt and stirred for onehour. The mixture was diluted with EtOAc and NaHCO₃ (aq) was added. Theorganic layer was washed with brine, dried over Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by silica gel columnchromatography (eluted with EtOAc in hexanes 0-100%) to give the desiredproduct (0.24 g, 63%) as brown oil. LCMS calc. for C₁₆H₂₀BF₂N₂O₂ (M+H)⁺:m/z=321.2. Found: 321.2.

Step 3:(3R,4R,5S)-3-Amino-1-{3-[({6-[2,6-difluoro-4-(1-methyl-H-pyrazol-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol

4-[3,5-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-methyl-1H-pyrazole(15.0 mg, 0.046 mmol), tert-butyl((3R,4R,5S)-1-(3-{[(6-bromo-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(Intermediate 1, 12.0 mg, 0.02 mmol), 1,4-dioxane (0.11 mL),N,N-diisopropylethylamine (11.2 mg, 0.09 mmol) and water (0.011 mL) weremixed together. The reaction mixture was flushed with nitrogen and thenbis(tri-tert-butylphosphine)palladium (4.0 mg, 0.009 mmol) was added.The mixture was sealed and heated at 120° C. for 2 h. The reactionmixture was filtered and concentrated under vacuum to give the crudeintermediate, which was treated with 4 N HCl in dioxane (2.0 mL). Thereaction mixture was stirred at room temperature for 2 h, and thesolvents were removed under vacuum. The residue was purified by prepLCMS (XBridge™ PrepC18 5 μm OBD™ column, 30×10 mm, 60 mL/min, gradientelution with MeCN and water with NH₄OH) to give the desired product as awhite powder. LCMS calc. for C₂₇H₂₉F₃N₇O (M+H)⁺: m/z=524.2. Found:524.3.

Example 95(3R,4R,5S)-3-Amino-1-(3-{[(3-isopropylfuro[3,2-b]pyridin-5-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-4-ol

Step 1. tert-Butyl[(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-(3-{[(3-isopropenylfuro[3,2-b]pyridin-5-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate

tert-Butyl((3R,4R,5S)-1-(3-{[(3-bromofuro[3,2-b]pyridin-5-yl)methyl]amino}pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(Intermediate 4, 20.0 mg, 0.0309 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (2.5 mg, 0.0032 mmol), potassium phosphate (20 mg, 0.096mmol) and magnet bar were placed in a vial with septum. The vial wasthen evacuated and backfilled with nitrogen three times. 1,4-Dioxane(2.5 mL) and degassed water (0.3 mL) were added to the reaction mixture.Finally 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (fromAldrich, 8.3 mg, 0.049 mmol) was added and the reaction mixture wasstirred at 65° C. for 1 h. Then the reaction mixture was diluted withEtOAc. The resulting solution was washed with brine, dried over Na₂SO₄and solvent evaporated. The crude product was purified by BiotageIsolera to give the desired compound (18 mg, 99%). LCMS calc. forC₃₃H₅₀N₅O₄Si (M+H)⁺ m/z=608.4. found: 608.4.

Step 2. tert-Butyl[(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-(3-{[(3-isopropylfuro[3,2-b]pyridin-5-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate

To a stirred solution of tert-butyl[(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-(3-{[(3-isopropenylfuro[3,2-b]pyridin-5-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(18 mg, 0.03 mmol) in methanol (10 mL) was added 5 w % of Pd on carbon(31 mg, 0.015 mmol). A vial was closed with septum and was connected toa balloon with hydrogen. After stirring at room temperature for 3 h, thereaction mixture was filtered through a pad of diatomaceous earth andthe solvent was evaporated under reduced pressure. The resulting crudeproduct was used in the next step without further purification (18 mg,99%). LCMS calc. for C₃₃H₅₂N₅O₄Si (M+H)⁺ m/z=610.4. found: 610.5.

Step 3.(3R,4R,5S)-3-Amino-1-(3-{[(3-isopropylfuro[3,2-b]pyridin-5-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-4-ol

tert-Butyl((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-(3-{[(3-isopropylfuro[3,2-b]pyridin-5-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(19 mg, 0.032 mmol) was dissolved in methanol (2 mL). Then 4.0 Msolution of HCl in dioxane (1 mL, 4 mmol) was added to the reactionmixture. The reaction mixture was stirred at room temperature overnight.Then the reaction mixture was neutralized by addition of the ammoniasolution and purified by RP-HPLC (water XBridge C18 column, 30 mm×100mm, 5 m particle size, gradient elution with acetonitrile/watercontaining 0.1% NH₄OH, at flow rate of 60 mL/min). LCMS calc. forC₂₂H₃₀N₅O₂ (M+H)⁺ m/z=396.2. found: 396.3.

Example 96(3R,4R,5S)-3-amino-1-(3-(((3-(2,6-difluoro-4-(hydroxymethyl)phenyl)furo[3,2-b]pyridin-5-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol

This compound was synthesized according to the procedures described inExample 95, using(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol(from Example 35 Step 1) to replace2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in Step 1. LCMScalc. for C₂₆H₂₈F₂N₅O₃ (M+H)⁺ m/z=496.2. found: 496.2.

Example 97(3R,4R,5S)-3-amino-1-(3-(((3-(2-fluoro-4-(hydroxymethyl)phenyl)furo[3,2-b]pyridin-5-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol

This compound was synthesized according to the procedures described inExample 95, using 2-fluoro-4-(hydroxymethyl)phenylboronic acid (fromCombi-Blocks) to replace2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in Step 1. LCMScalc. for C₂₆H₂₉FN₅O₃ (M+H)⁺ m/z=478.2. found: 478.2.

Example 984-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-N-[(3-isopropylfuro[3,2-b]pyridin-5-yl)methyl]pyridin-3-amine

Step 1. tert-Butyl[(3S,5R)-1-(3-{[(3-isopropenylfuro[3,2-b]pyridin-5-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate

tert-Butyl[(3S,5R)-1-(3-{[(3-bromofuro[3,2-b]pyridin-5-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(Intermediate 5, 20.0 mg, 0.0387 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (23.0 mg, 0.0039 mmol), potassium phosphate (25 mg, 0.12mmol) and magnet bar were placed in a vial with septum. The vial wasthen evacuated and backfilled with nitrogen three times. 1,4-Dioxane(2.5 mL) and degassed water (0.3 mL) were added to the reaction mixture.Finally 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10. mg,0.062 mmol) was added and the reaction mixture was stirred at 65° C. for1 h. Then the reaction mixture was diluted with EtOAc. The resultingsolution was washed with brine, dried over Na₂SO₄ and solventevaporated. The crude product was purified by Biotage Isolera to givethe desired compound (19 mg, 99%). LCMS calc. for C₂₇H₃₆N₅O₃ (M+H)⁺m/z=478.3. found: 478.3.

Step 2. tert-Butyl[(3S,5R)-1-(3-{[(3-isopropylfuro[3,2-b]pyridin-5-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate

To a stirred solution of tert-butyl[(3S,5R)-1-(3-{[(3-isopropenylfuro[3,2-b]pyridin-5-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(19 mg, 0.040 mmol) in methanol (10 mL) was added 5 w % of Pd on carbon(31 mg, 0.015 mmol). A vial was closed with septum and was connected toa balloon with hydrogen. After stirring at room temperature for 3 h, thereaction was filtered through a pad of diatomaceous earth and thesolvent was evaporated under reduced pressure. The resulting crudeproduct was used in the next step without further purification (18 mg,99%). LCMS calc. for C₂₇H₃₈N₅O₃ (M+H)⁺ m/z=480.3. found: 480.3.

Step 3.4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-N-[(3-isopropylfuro[3,2-b]pyridin-5-yl)methyl]pyridin-3-amine

tert-Butyl[(3S,5R)-1-(3-{[(3-isopropylfuro[3,2-b]pyridin-5-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(18 mg, 0.038 mmol) was dissolved in methanol (2 mL). Then 4.0 Msolution of HCl in dioxane (1 mL, 4 mmol) was added to the reactionmixture. The reaction mixture was stirred at room temperature overnight.Then the reaction mixture was neutralized by addition of the ammoniasolution and purified by RP-HPLC (water XBridge C18 column, 30 mm×100mm, 5 μm particle size, gradient elution with acetonitrile/watercontaining 0.1% NH₄OH, at flow rate of 60 mL/min). LCMS calc. forC₂₂H₃₀N₅O (M+H)⁺ m/z=380.2. found: 380.2. ¹H NMR (400 MHz, DMSO-d6) δ8.06 (d, J=0.9 Hz, 1H), 7.96 (d, J=8.5 Hz, 1H), 7.86 (s, 1H), 7.83 (d,J=5.0 Hz, 1H), 7.36 (d, J=8.5 Hz, 1H), 6.86 (d, J=5.1 Hz, 1H), 5.76 (t,J=5.5 Hz, 1H), 4.65-4.51 (m, 2H), 3.26-3.24 (m, 2H), 3.22-3.15 (m, 2H),3.07-2.94 (m, 1H), 2.16 (t, J=10.6 Hz, 1H), 2.08 (t, J=11.0 Hz, 1H),2.02-1.89 (m, 2H), 1.39 (d, J=6.9 Hz, 6H), 0.90 (d, J=6.3 Hz, 3H),0.87-0.76 (m, 1H) ppm.

Example 99(4-(5-((4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)furo[3,2-b]pyridin-3-yl)-3,5-difluorophenyl)methanol

This compound was synthesized using similar procedures as described inExample 98, using(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanolto replace 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane inStep 1. LCMS calc. for C₂₆H₂₈F₂N₅O₂ (M+H)⁺ m/z=480.2. found: 480.2. ¹HNMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.18 (d, J=8.6 Hz, 1H), 7.86 (s,1H), 7.83 (d, J=5.0 Hz, 1H), 7.48 (d, J=8.6 Hz, 1H), 7.23 (d, J=8.2 Hz,2H), 6.79 (d, J=5.1 Hz, 1H), 5.84-5.77 (m, 1H), 4.65 (s, 2H), 4.64-4.42(m, 2H), 3.52 (s, 1H), 3.14-3.03 (m, 2H), 2.48-2.41 (m, 1H), 2.17 (t,J=10.5 Hz, 2H), 1.81 (t, J=11.2 Hz, 2H), 1.67 (d, J=12.2 Hz, 1H), 1.41(s, 1H), 0.71 (d, J=6.6 Hz, 3H), 0.68-0.60 (m, 1H) ppm.

Example 100(4-(5-((4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)furo[3,2-b]pyridin-3-yl)-3-fluorophenyl)methanol

This compound was synthesized according to the procedures described inExample 98, using (2-fluoro-4-(hydroxymethyl)phenylboronic acid toreplace 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in Step 1.LCMS calc. for C₂₆H₂₉FN₅O₂ (M+H)⁺ m/z=462.2. found: 462.2. ¹H NMR (400MHz, DMSO-d6) δ 8.64 (d, J=2.5 Hz, 1H), 8.45 (t, J=7.9 Hz, 1H), 8.14 (d,J=8.6 Hz, 1H), 7.85 (s, 1H), 7.81 (d, J=5.0 Hz, 1H), 7.48 (d, J=8.6 Hz,1H), 7.34-7.21 (m, 2H), 6.83 (d, J=5.1 Hz, 1H), 5.68 (t, J=5.5 Hz, 1H),4.70-4.54 (m, 4H), 3.23 (d, J=7.0 Hz, 2H), 3.13 (d, J=9.2 Hz, 2H),2.89-2.74 (m, 1H), 2.13 (t, J=10.6 Hz, 1H), 1.99 (t, J=11.1 Hz, 1H),1.84-1.66 (m, 2H), 0.79 (d, J=6.5 Hz, 3H), 0.72 (q, J=11.8 Hz, 1H) ppm.

Example 101(3R,4R,5S)-3-Amino-1-(3-{[(3-cyclopropylfuro[3,2-b]pyridin-5-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-4-ol

Step 1. tert-Butyl[(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-(3-{[(3-cyclopropylfuro[3,2-b]pyridin-5-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate

tert-Butyl((3R,4R,5S)-1-(3-{[(3-bromofuro[3,2-b]pyridin-5-yl)methyl]amino}pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(Intermediate 4, 20.0 mg, 0.0309 mmol), potassiumcyclopropyltrifluoroborate (from Aldrich, 9.2 mg, 0.062 mmol), cesiumcarbonate (30.2 mg, 0.0928 mmol), palladium acetate (1.0 mg, 0.0046mmol) and di-1-adamantyl(butyl)phosphine (3.3 mg, 0.0093 mmol) wereplaced in a vial. The vial was sealed and evacuated and filled withnitrogen three times. Toluene (1.0 mL) and water (100 μL) were added andthe reaction mixture was stirred at 100° C. overnight. Then the reactionmixture was diluted with EtOAc. Obtained solution was washed with brine,dried over Na₂SO₄ and solvent was evaporated under reduced pressure. Theresulting crude product was used in the next step without furtherpurification. LCMS calc. for C₃₃H₅₀N₅O₄Si (M+H)⁺ m/z=608.4. found:608.4.

Step 2.(3R,4R,5S)-3-Amino-1-(3-{[(3-cyclopropylfuro[3,2-b]pyridin-5-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-4-ol

tert-Butyl[(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-(3-{[(3-cyclopropylfuro[3,2-b]pyridin-5-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(18 mg, 0.03 mmol) was dissolved in methanol (2 mL). Then 4.0 M solutionof HCl in dioxane (1 mL, 4 mmol) was added to the reaction mixture. Thereaction mixture was stirred at room temperature overnight. Then thereaction mixture was neutralized by addition of the ammonia solution andpurified by RP-HPLC (water XBridge C18 column, 30 mm×100 mm, 5 mparticle size, gradient elution with acetonitrile/water containing 0.1%NH₄OH, at flow rate of 60 mL/min). LCMS calc. for C₂₂H₂₈N₅O₂ (M+H)⁺m/z=394.2. found: 394.2.

Example 1024-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-N-[(3-cyclopropylfuro[3,2-b]pyridin-5-yl)methyl]pyridin-3-amine

Step 1. tert-Butyl[(3S,5R)-1-(3-{[(3-cyclopropylfuro[3,2-b]pyridin-5-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate

tert-Butyl[(3S,5R)-1-(3-{[(3-bromofuro[3,2-b]pyridin-5-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(Intermediate 5, 16.0 mg, 0.0309 mmol), potassiumcyclopropyltrifluoroborate (9.2 mg, 0.062 mmol), cesium carbonate (30.2mg, 0.0928 mmol), palladium acetate (1.0 mg, 0.0046 mmol) anddi-1-adamantyl(butyl)phosphine (3.3 mg, 0.0093 mmol) were placed in avial. The vial was sealed and evacuated and filled with nitrogen threetimes. Toluene (1.0 mL) and water (100 μL) were added and the reactionmixture was stirred at 100° C. overnight. Then the reaction mixture wasdiluted with EtOAc. Obtained solution was washed with brine, dried overNa₂SO₄ and solvent was evaporated under reduced pressure. The resultingcrude product was used in the next step without further purification.LCMS calc. for C₂₇H₃₆N₅O₃(M+H)⁺ m/z=478.3. found: 478.3.

Step 2.4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-N-[(3-cyclopropylfuro[3,2-b]pyridin-5-yl)methyl]pyridin-3-amine

tert-Butyl[(3S,5R)-1-(3-{[(3-cyclopropylfuro[3,2-b]pyridin-5-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(14 mg, 0.03 mmol) was dissolved in methanol (2 mL). Then 4.0 M solutionof HCl in dioxane (1 mL, 4 mmol) was added to the reaction mixture. Thereaction mixture was stirred at room temperature overnight. Then thereaction mixture was neutralized by addition of the ammonia solution andpurified by RP-HPLC (water XBridge C18 column, 30 mm×100 mm, 5 μmparticle size, gradient elution with acetonitrile/water containing 0.1%NH₄OH, at flow rate of 60 mL/min). LCMS calc. for C₂₂H₂₈N₅O (M+H)⁺m/z=378.2. found: 378.2. ¹H NMR (400 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.94(d, J=8.5 Hz, 1H), 7.85-7.79 (m, 2H), 7.34 (d, J=8.5 Hz, 1H), 6.85 (d,J=5.1 Hz, 1H), 5.72 (t, J=5.4 Hz, 1H), 4.59-4.53 (m, 2H), 3.27 (d, J=8.4Hz, 1H), 3.20-3.16 (m, 1H), 3.06-2.92 (m, 1H), 2.21-1.85 (m, 6H),1.01-0.91 (m, 4H), 0.89 (d, J=6.3 Hz, 3H), 0.85-0.72 (m, 1H) ppm.

Example 1031-(4-{6-[({4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenoxy)-2-methylpropan-2-ol

Step 1. 1-(3,5-Difluorophenoxy)-2-methylpropan-2-ol

A mixture of 3,5-difluorophenol (from Aldrich, 1.0 g, 7.7 mmol),2,2-dimethyloxirane (from Aldrich, 1.9 mL, 23 mmol) and potassiumcarbonate (2.1 g, 15 mmol) in N,N-dimethylformamide (8 mL) wasmicrowaved at 150° C. for 30 min. The reaction mixture was diluted withwater, extracted with EtOAc, concentrated and purified on silica gelcolumn (gradient elution with 0-50% EtOAc/hexanes) to give the desiredproduct (1.6 g, 100%). LCMS calc. for C₁₀H₁₃F₂O₂ (M+H)⁺ m/z=203.1.found: 203.1.

Step 2.1-[3,5-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-2-methylpropan-2-ol

To a mixture of 1-(3,5-difluorophenoxy)-2-methylpropan-2-ol (1.6 g, 7.9mmol) in tetrahydrofuran (31 mL) cooled at −78° C. was slowly added 2.5M n-butyllithium in hexanes (7.9 mL, 20 mmol). When addition completedthe mixture was stirred at −78° C. for 1 h.2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.84 mL, 23.7mmol) was then added to the reaction mixture in one portion. Thereaction mixture was allowed to warm to room temperature and stirred atthat temperature for 1 h. The reaction mixture was poured into a mixtureof EtOAc and saturated aqueous NaHCO₃ solution. The organic layer waswashed with brine, dried over MgSO₄ and concentrated to give the product(2.6 g, 100%), which was used in the next step directly. LCMS calc. forC₁₆H₂₄BF₂O₄(M+H)⁺ m/z=329.2. found: 329.2.

Step 3. Methyl6-[2,6-difluoro-4-(2-hydroxy-2-methylpropoxy)phenyl]-5-fluoropyridine-2-carboxylate

A mixture of methyl 6-bromo-5-fluoropyridine-2-carboxylate (1.8 g, 7.5mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (0.62 g, 0.79 mmol) and cesium carbonate (5.2 g, 16 mmol) wasevacuated and backfilled with nitrogen three times. A solution of1-[3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-2-methylpropan-2-ol(2.6 g, 7.9 mmol) in 1,4-dioxane (19.74 mL) was added, followed by theaddition of degassed water (9.87 mL). The reaction mixture was stirredat 55° C. overnight. The reaction mixture was filtered, concentrated,diluted with EtOAc, washed with water, concentrated and purified onsilica gel column (gradient elution with 0-100% EtOAC/hexanes) to givethe desired product (1.0 g, 37%). LCMS calc. for C₁₇H₁₇F₃NO₄ (M+H)⁺m/z=356.1. found: 356.1.

Step 4.6-[2,6-Difluoro-4-(2-hydroxy-2-methylpropoxy)phenyl]-5-fluoropyridine-2-carboxylicacid

A mixture of methyl6-[2,6-difluoro-4-(2-hydroxy-2-methylpropoxy)phenyl]-5-fluoropyridine-2-carboxylate(1.0 g, 2.8 mmol) and 1.0 M sodium hydroxide in water (11 mL, 11 mmol)in tetrahydrofuran (20 mL)/methanol (20 mL) was stirred at roomtemperature for 1 h. The mixture was concentrated, and the residue wasacidified by addition of aqueous 4N HCl solution. The mixture wasextracted with EtOAc. The combined organic layers were dried over MgSO₄and concentrated to give the crude product (0.8 g, 80%). LCMS calc. forC₁₆H₁₅F₃NO₄ (M+H)⁺ m/z=342.1. found: 342.0.

Step 5.1-{3,5-Difluoro-4-[3-fluoro-6-(hydroxymethyl)pyridin-2-yl]phenoxy}-2-methylpropan-2-ol

To a mixture of6-[2,6-difluoro-4-(2-hydroxy-2-methylpropoxy)phenyl]-5-fluoropyridine-2-carboxylicacid (0.80 g, 2.3 mmol) and triethylamine (0.343 mL, 2.46 mmol) intetrahydrofuran (10 mL) was added tert-butyl chloridocarbonate (0.322mL, 2.46 mmol) dropwise. The reaction mixture was stirred for 1 h. Theprecipitate was collected by filtration. The filtrate was cooled in anice bath and a solution of sodium tetrahydroborate (0.18 g, 4.7 mmol) inwater (0.8 mL) was added dropwise. The reaction mixture was stirred for30 min, then quenched with aqueous saturated NaHCO₃ solution, extractedwith EtOAc. The organic layers were combined, concentrated and purifiedon silica gel column (gradient elution with 0-100% EtOAc/hexanes) togive the desired product (0.47 g, 61%). LCMS calc. for C₁₆H₁₇F₃NO₃(M+H)⁺ m/z=328.1. found: 328.2.

Step 6.6-(2,6-difluoro-4-(2-hydroxy-2-methylpropoxy)phenyl)-5-fluoropicolinaldehyde

To a mixture of1-{3,5-difluoro-4-[3-fluoro-6-(hydroxymethyl)pyridin-2-yl]phenoxy}-2-methylpropan-2-ol(470 mg, 1.4 mmol) and pyridine (0.14 mL, 1.7 mmol) in DCM (9 mL) wasadded Dess-Martin periodinane (0.67 g, 1.6 mmol) at 0° C. The reactionmixture was stirred at room temperature for 2 h. The reaction mixturewas quenched with aqueous saturated NaHCO₃ solution and aqueoussaturated Na₂S₂O₃ solution (1:1), extracted with DCM. The combinedorganic layers were concentrated and purified on silica gel (gradientelution with 0-100% EtOAc/hexanes) to give the desired product (0.44 g,94%). LCMS calc. for C₁₆H₁₅F₃NO₃ (M+H)⁺ m/z=326.1. found: 326.1.

Step 7. tert-Butyl((3S,5R)-1-{3-[({6-[2,6-difluoro-4-(2-hydroxy-2-methylpropoxy)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate

A mixture of tert-butyl[(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(Prepared in Intermediate 2, Step 6; 47 mg, 0.15 mmol),6-(2,6-difluoro-4-(2-hydroxy-2-methylpropoxy)phenyl)-5-fluoropicolinaldehyde(51 mg, 0.16 mmol) and acetic acid (7.2 μL, 0.13 mmol) in toluene (5.6mL) was heated at 100° C. for 2 h. Then solvent was evaporated andmethanol (5.6 mL) was added. After addition of sodium tetrahydroborate(12 mg, 0.32 mmol) at 0° C., the resulting reaction mixture was stirredfor 10 min. The solvent was removed, and the residue was diluted withwater and extracted with EtOAc. The combined organic layers were driedover MgSO₄ and concentrated to give the crude product (32 mg, 33%). LCMScalc. for C₃₂H₄₁F₃N₅O₄(M+H)⁺ m/z=616.1. found: 616.3.

Step 8.1-(4-{6-[({4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenoxy)-2-methylpropan-2-ol

tert-Butyl((3S,5R)-1-{3-[({6-[2,6-difluoro-4-(2-hydroxy-2-methylpropoxy)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate(0.032 g, 0.052 mmol) was treated with 4.0 M hydrogen chloride indioxane (0.065 mL, 0.26 mmol) in DCM (1 mL) at room temperature for 1 h.The reaction mixture was concentrated to dryness and the resultantresidue was purified on prep-LCMS (Waters Sunfire C18, 5 um particlesize, 30×100 mm; mobile phases: water (0.1% TFA)/acetonitrile at a flowrate of 60 ml/min; Gradient: 8.5-28.5% acetonitrile in 5 min) to givethe desired product (5 mg, 19%). LCMS calc. for C₂₇H₃₃F₃N₅O₂(M+H)⁺m/z=516.3. found: 516.3.

Example 104(3R,4R,5S)-3-Amino-1-{3-[({6-[2,6-difluoro-4-(2-hydroxy-2-methylpropoxy)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol

Step 1. tert-Butyl((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-{3-[({6-[2,6-difluoro-4-(2-hydroxy-2-methylpropoxy)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate

A mixture of tert-butyl((3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(Prepared in Intermediate 1, Step 11; 67 mg, 0.15 mmol),6-(2,6-difluoro-4-(2-hydroxy-2-methylpropoxy)phenyl)-5-fluoropicolinaldehyde(Prepared in Example 103, Step 6; 51 mg, 0.16 mmol) and acetic acid (7.2L, 0.13 mmol) in toluene (5.6 mL) was heated at 100° C. for 2 h. Thensolvent was evaporated and methanol (5.6 mL) was added. After additionof sodium tetrahydroborate (12 mg, 0.32 mmol) at 0° C., the resultingreaction mixture was stirred for 10 min. The solvent was removed, theresidue was diluted with water, extracted with EtOAc. The combinedorganic layers were dried over MgSO₄ and concentrated under reducedpressure to give the crude product (38 mg, 33%). LCMS calc. forC₃₈H₅₅F₃N₅O₅Si (M+H)⁺ m/z=746.4. found: 746.3.

Step 2.(3R,4R,5S)-3-Amino-1-{3-[({6-[2,6-difluoro-4-(2-hydroxy-2-methylpropoxy)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol

tert-Butyl((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-{3-[({6-[2,6-difluoro-4-(2-hydroxy-2-methylpropoxy)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate(0.038 g, 0.052 mmol) was treated with 4.0 M hydrogen chloride indioxane (0.065 mL, 0.26 mmol) in DCM (1 mL) at room temperature for 1 h.The mixture was concentrated to dryness and the residue was purified onprep-LCMS (Waters Sunfire C18, 5 um particle size, 30×100 mm; mobilephases: water (0.1% TFA)/acetonitrile at a flow rate of 60 ml/min;Gradient: 8.5-28.5% acetonitrile in 5 min) to give the desired product(5 mg, 18%). LCMS calc. for C₂₇H₃₃F₃N₅O₃(M+H)⁺ m/z=532.3. found: 532.2.

Example 1052-(4-{6-[({4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)propan-2-ol

Step 1. 2-(3,5-Difluorophenyl)propan-2-ol

To a solution of acetone (0.20 mL, 2.7 mmol) in tetrahydrofuran (4.1 mL)cooled at 0° C. was added 0.5 M bromo(2,6-difluorophenyl)magnesium inTHF (from Aldrich, 6.0 mL, 3.0 mmol) slowly. The reaction was stirredovernight, then quenched with aq. NH₄Cl solution, extracted with EtOAc.The combined organic extracts were washed with brine, dried over MgSO₄and concentrated to give the crude product (0.34 g, 72%), which was usedin the next step without further purification.

Step 2.2-[3,5-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propan-2-ol

To a mixture of 2-(3,5-difluorophenyl)propan-2-ol (340 mg, 2.0 mmol) intetrahydrofuran (7.8 mL) cooled at −78° C. was slowly added 2.5 Mn-butyllithium in hexanes (2.0 mL, 4.9 mmol). The mixture was stirred at−78° C. for 1 h. 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(from Aldrich, 1.21 mL, 5.92 mmol) was then added in one portion. Themixture was allowed to warm up to rt and stirred at rt for 1 h, thenworked up in EtOAc and NaHCO₃ solution. The organic layer was washedwith brine, dried over MgSO₄ and concentrated to give the crude product(0.5 g, 90%), which was used in the next step without purification.

Step 3. Methyl6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxylate

A mixture of methyl 6-bromo-5-fluoropyridine-2-carboxylate (230 mg, 0.97mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (76 mg, 0.097 mmol) and cesium carbonate (0.63 g, 1.9 mmol) wasevacuated and backfilled with nitrogen three times. A solution of2-[3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propan-2-ol(290 mg, 0.97 mmol) in 1,4-dioxane (2.424 mL) was added, followed by theaddition of degassed water (1.21 mL). The reaction mixture was stirredat 55° C. for 1 h. The reaction mixture was purified on silica gel(gradient elution with 0-100% EtOAC/hexanes) to give the desired product(100 mg, 32%). LCMS calc. for C₁₆H₁₅F₃NO₃ (M+H)⁺ m/z=326.1. found:326.1.

Step 4.6-[2,6-Difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxylicacid

A mixture of methyl6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxylate(99 mg, 0.30 mmol) and 1.0 M sodium hydroxide in water (2 mL, 2 mmol) intetrahydrofuran (2 mL)/methanol (2 mL) was stirred at room temperaturefor 1 h. The reaction mixture was concentrated, and the residue wasacidified by addition of aqueous 4N HCl solution. The mixture wasextracted with EtOAc. The combined extracted were dried over MgSO₄ andconcentrated to give the crude product (90 mg, 100%). LCMS calc. forC₁₅H₁₃F₃NO₃ (M+H)⁺ m/z=312.1. found: 312.0.

Step 5.2-{3,5-Difluoro-4-[3-fluoro-6-(hydroxymethyl)pyridin-2-yl]phenyl}propan-2-ol

To a mixture of6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxylicacid (0.17 g, 0.55 mmol) and triethylamine (0.0799 mL, 0.573 mmol) intetrahydrofuran (3 mL) was added tert-butyl chloridocarbonate (0.075 mL,0.573 mmol) dropwise. The reaction mixture was stirred for 1 h. Theprecipitate was removed by filtration. The filtrate was cooled in an icebath and a solution of sodium tetrahydroborate (0.041 g, 1.1 mmol) inwater (0.2 mL) was added dropwise. The reaction mixture was stirred for1 h, and then quenched with saturated aq. NaHCO₃, extracted with EtOAc.The combined organic layers were concentrated under reduced pressure andthe resultant residue was purified on silica gel (gradient elution with0-100% EtOAc/hexanes) to give the desired product (70 mg, 40%). LCMScalc. for C₁₅H₁₅F₃NO₂(M+H)⁺ m/z=298.1. found: 298.1.

Step 6.6-[2,6-Difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carbaldehyde

To a mixture of2-{3,5-difluoro-4-[3-fluoro-6-(hydroxymethyl)pyridin-2-yl]phenyl}propan-2-ol(0.070 g, 0.24 mmol) and pyridine (0.023 mL, 0.28 mmol) in DCM (2 mL)was added Dess-Martin periodinane (0.11 g, 0.26 mmol) at 0° C. Thereaction mixture was stirred for 2 h. The reaction mixture was quenchedwith a mixture of aqueous saturated NaHCO₃ solution and aqueoussaturated Na₂S₂₀₃ solution (1:1), extracted with DCM. The combinedorganic layers were concentrated under reduced pressure and purified onsilica gel (gradient elution with 0-100% EtOAc/hexanes) to give thedesired product (70 mg, 100%). LCMS calc. for C₁₅H₁₃F₃NO₂ (M+H)⁺m/z=296.1. found: 296.1.

Step 7. tert-Butyl((3S,5R)-1-{3-[({6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate

A mixture of tert-butyl[(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(Prepared in Intermediate 2, Step 6; 0.035 g, 0.12 mmol),6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carbaldehyde(35 mg, 0.12 mmol) and acetic acid (5.5 μL, 0.096 mmol) in toluene (4.2mL) was heated at 100° C. for 2 h. Then solvent was evaporated andmethanol (4.2 mL) was added. After addition of sodium tetrahydroborate(9.1 mg, 0.24 mmol) at 0° C., the reaction mixture was stirred for 10min. The solvent was removed, and the resultant residue was diluted withwater, extracted with EtOAc. The organic layers were combined, driedover MgSO₄ and concentrated to give the crude product (30 mg, 48%). LCMScalc. for C₃₁H₃₉F₃N₅O₃(M+H)⁺ m/z=586.3. found: 586.2.

Step 8.2-(4-{6-[({4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)propan-2-ol

tert-Butyl((3S,5R)-1-{3-[({6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate(0.030 g, 0.052 mmol) was treated with 4.0 M hydrogen chloride indioxane (0.065 mL, 0.26 mmol) in DCM (1 mL) at room temperature for 1 h.The reaction mixture was concentrated to dryness and the residue waspurified on prep-LCMS (Waters Sunfire C18, 5 um particle size, 30×100mm; mobile phases: water (0.1% TFA)/acetonitrile at a flow rate of 60ml/min; Gradient: 8.5-28.5% acetonitrile in 5 min) to give the desiredproduct (5 mg, 20%). LCMS calc. for C₂₆H₃₁F₃N₅O (M+H)⁺ m/z=486.2. found:486.2.

Example 106(3R,4R,5S)-3-Amino-1-{3-[({6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol

Step 1. tert-Butyl((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-{3-[({6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate

A mixture of tert-butyl((3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(Prepared in Intermediate 1, Step 11; 0.050 g, 0.12 mmol),6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carbaldehyde(Prepared in Example 105, Step 4; 35 mg, 0.12 mmol) and acetic acid (5.5μL, 0.096 mmol) in toluene (4.2 mL) was heated at 100° C. for 2 h. Thensolvent was evaporated and methanol (4.2 mL) was added. After additionof sodium tetrahydroborate (9.1 mg, 0.24 mmol) at 0° C., the reactionmixture was stirred for 10 min. The solvent was removed, diluted withwater, extracted with EtOAc. The organic extracts were combined, driedover MgSO₄ and concentrated to give the crude product (37 mg, 46%). LCMScalc. for C₃₇H₅₃F₃N₅O₄Si (M+H)⁺ m/z=716.4. found: 716.3.

Step 2.(3R,4R,5S)-3-Amino-1-{3-[({6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol

tert-Butyl((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-{3-[({6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate(0.037 g, 0.052 mmol) was treated with 4.0 M hydrogen chloride indioxane (0.065 mL, 0.26 mmol) in DCM (1 mL) at room temperature for 1 h.The mixture was concentrated to dryness under reduced pressure and theresidue was purified on prep-LCMS (Waters Sunfire C18, 5 um particlesize, 30×100 mm; mobile phases: water (0.1% TFA)/acetonitrile at a flowrate of 60 ml/min; Gradient: 8.5-28.5% acetonitrile in 5 min) to givethe desired product (5 mg, 19%). LCMS calc. for C₂₆H₃₁F₃N₅O₂(M+H)⁺m/z=502.2. found: 502.2.

Example 1074-{2-[({4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]quinolin-7-yl}-3-fluoro-1-methylpyridin-2(1H)-one

Step 1. tert-Butyl((3R,4R,5S)-1-(3-{[(7-bromoquinolin-2-yl)methyl]amino}pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate

A mixture tert-butyl ((3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(Prepared in Intermediate 1, Step 11; 300 mg, 0.68 mmol),7-bromoquinoline-2-carbaldehyde (Prepared in Example 91, Step 2; 200 mg,0.846 mmol) and acetic acid (39 μL, 0.68 mmol) in Toluene (30 mL) washeated at 100° C. for 2 h. Then solvent was evaporated and methanol (30mL) was added. After addition of sodium tetrahydroborate (65 mg, 1.7mmol) at 0° C., the reaction mixture was stirred for 1 h. The solventwas removed. The residue was diluted with water, then extracted withEtOAc. The combined organic layers were dried over MgSO₄, concentratedand purified by Combi-flash Chromatography with 20-100% EtOAc/hexane aseluents to give the product (0.40 g, 89%). LCMS calc. for C₃₂H₄₇BrN₅O₃Si(M+H)⁺ m/z: 656.3. found: 656.1.

Step 2. tert-Butyl{(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methyl-1-[3-({[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-yl]methyl}amino)pyridin-4-yl]piperidin-3-yl}carbamate

A mixture of tert-butyl ((3R,4R,5S)-1-(3-{[(7-bromoquinolin-2-yl)methyl]amino}pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate(0.098 g, 0.15 mmol),4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl](0.0454 g,0.179 mmol), potassium acetate (0.029 g, 0.30 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.011 g,0.015 mmol) in 1,4-dioxane (0.5 mL) was vacuumed and refilled with N₂for 3 times, then sealed and heated at 95° C. for 2 h. The reactionmixture was cooled to r.t and used directly in the next step withoutfurther purification. LCMS calc. for C₃₈H₅₉BN₅O₅Si (M+H)⁺ m/z: 704.4.found: 704.4.

Step 3. 3-Fluoro-4-iodopyridin-2(1H)-one

A mixture of 2,3-difluoro-4-iodopyridine (from Ark Pharm, 3.0 g, 12mmol) in acetic acid (30 mL) and water (15 mL) was heated to refluxovernight. Most of the solvent was removed by vacuum and the remainingwas neutralized with aq. NaHCO₃ and extracted by EtOAc. The organiclayers were combined, dried and concentrated. The white solid crudeproduct obtained (2.5 g, 84%) was used directly in the next step withoutfurther purifications. LCMS calc. for C₅H₄FINO (M+H)⁺ m/z=239.9. found,240.0.

Step 4. 3-Fluoro-4-iodo-1-methylpyridin-2(1H)-one

To a mixture of 3-fluoro-4-iodopyridin-2(1H)-one (2.5 g, 10 mmol) andpotassium carbonate (3.5 g, 25 mmol) in N,N-dimethylformamide (10 mL)was added iodomethane (3.9 g, 25 mmol). The reaction mixture was stirredat rt overnight, then worked up with aq NaHCO₃ and EtOAc. The organiclayer was separated, dried over Na₂SO₄ and concentrated by vacuum. Theresulting residue was purified with Combi-flash chromatography (elutingwith 0-100% EtOAc in hexanes) to give 2.0 g (77%) of the desiredproduct. LCMS calc. for C₆H₆FINO (M+H)⁺ m/z=253.9. found: 254.1.

Step 5.4-{2-[({4-[(3R,4R,5S)-3-Amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]quinolin-7-yl}-3-fluoro-1-methylpyridin-2(1H)-one

In a sealed tube a mixture of tert-butyl{(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methyl-1-[3-({[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-yl]methyl}amino)pyridin-4-yl]piperidin-3-yl}carbamate(100 mg, 0.1 mmol), 3-fluoro-4-iodo-1-methylpyridin-2(1H)-one (48 mg,0.19 mmol), and N,N-diisopropylethylamine (0.076 mL, 0.44 mmol) in1,4-dioxane (4.0 mL) and water (0.40 mL) was stirred together andflushed with N₂ bubble for 5 min beforebis(tri-t-butylphosphine)palladium (20 mg, 0.04 mmol) was added to thereaction mixture. The reaction mixture was then heated at 110° C. for 1h. The crude was purified by silica gel column chromatography (40 gcolumn, gradient elution with 0-100% EtOAc in hexanes, 5% MeOH)) to givethe desired Suzuki product.

Above product was dissolved in small amount of MeOH and 4N HCl was addedand the resultant reaction mixture was stirred for 1 h at roomtemperature Most of solvent was removed under reduced pressure and theresulting residue was purified with prep-HPLC (Waters Sunfire C18, 5 umparticle size, 30×100 mm; mobile phases: water (0.15% ammoniumhydroxide)/acetonitrile at a flow rate of 60 ml/min) to give the desiredproduct (10.0 mg, 15%). LCMS calc. for C₂₇H₂₈FN₆O₃(M+H)⁺ m/z: 503.2.found: 503.1.

Example 1082-[({4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-6-(2,6-difluorophenyl)-5-fluoropyridin-3-amine

Step 1. tert-Butyl[6-(2,6-difluorophenyl)-5-fluoro-2-(hydroxymethyl)pyridin-3-yl]carbamate

To a mixture of3-[(tert-butoxycarbonyl)amino]-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylicacid (from Infinity, 700 mg, 2 mmol) and triethylamine (278 μL, 2.00mmol) in tetrahydrofuran (14 mL) was added isobutyl chloroformate (0.259mL, 2.00 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30min. The resulting precipitate was removed by filtration. To thefiltrate was added sodium tetrahydroborate (140 mg, 3.8 mmol) in water(0.9 mL). The reaction mixture was stirred at r.t for 1 h, then quenchedwith water, extracted with EtOAc. The combined organic layers werewashed with brine, dried and solvent evaporated. The residue waspurified with combi-flash using 0-50% hexanes/EtOAc to give the desiredproduct (230 mg, 30%). LCMS calc. for C₁₇H₁₈F₃N₂O₃(M+H)⁺ m/z: 355.1.found: 355.1.

Step 2. tert-Butyl[6-(2,6-difluorophenyl)-5-fluoro-2-formylpyridin-3-yl]carbamate

To a stirred solution of tert-butyl[6-(2,6-difluorophenyl)-5-fluoro-2-(hydroxymethyl)pyridin-3-yl]carbamate(200 mg, 0.58 mmol) in DCM (4 mL, 60 mmol) at 0° C. was added pyridine(56 μL, 0.69 mmol) and Dess-Martin periodinane (257 mg, 0.605 mmol). Thereaction mixture was stirred overnight at room temperature Solution ofNaHCO₃ and Na₂S₂O₃ was added and the resulting reaction mixture wasstirred for 30 min, and then extracted with DCM. The combined organiclayers were dried, concentrated under reduced pressure. The residue waspurified by Combi-flash chromatography using 10-50% EtOAc in hexanes aseluents to give the desired product (180 mg, 90%). LCMS calc. forC₁₇H₁₆F₃N₂O₃(M+H)⁺ m/z: 353.1. found: 353.1.

Step 3.2-[({4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-6-(2,6-difluorophenyl)-5-fluoropyridin-3-amine

tert-Butyl [(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate (Preparedin Intermediate 2, Step 6; 14 mg, 0.046 mmol) and tert-butyl[6-(2,6-difluorophenyl)-5-fluoro-2-formylpyridin-3-yl]carbamate (18 mg,0.050 mmol) were dissolved in toluene (2.0 mL) and catalitic around ofacetic acid was added. The reaction mixture was heated at 100° C. for 2h. Then solvent was evaporated and methanol (2.0 mL) was added. Afteraddition of sodium tetrahydroborate (4.3 mg, 0.11 mmol), the reactionwas stirred for 30 min, and then concentrated under reduced pressure.The residue was dissolved in methanol (0.5 mL) and 4.0 M hydrogenchloride in dioxane (2 mL, 8 mmol) was added. The reaction mixture wasstirred for 30 min. Solvent was removed and the resulting residue waspurified with prep-HPLC (Waters Sunfire C18, 5 um particle size, 30×100mm; mobile phases: water (0.1% TFA)/acetonitrile at a flow rate of 60ml/min) to give the desired product (5 mg, 30%). LCMS calc. forC₂₃H₂₇F₂N₆ (M+H)⁺ m/z: 425.2. found: 425.1. ¹H NMR (DMSO-d₆, 300 MHz): δ8.05 (s, 1H); 7.85 (d, 1H); 7.60 (m, 1H); 7.20 (t. 2H); 7.00 (d, 1H);6.80 (d, 1H); 6.05 (s, 2H); 5.90 (m, 1H); 4.25 (d, 1H); 4.15 (d, 1H);3.10 (d, 2H); 2.65 (m, 1H); 2.15 (t, 1H); 1.85 (t, 1H); 1.55 (m, 4H);0.65 (m, 4H) ppm.

Example 1092-[({4-[(3S,5R)-3-Amino-5-(trifluoromethyl)piperidin-1-yl]pyridin-3-yl}amino)methyl]-6-(2,6-difluorophenyl)-5-fluoropyridin-3-amine

tert-Butyl[(3S,5R)-1-(3-aminopyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate(Prepared in Intermediate 3, Step 4; 16 mg, 0.050 mmol) and tert-butyl[6-(2,6-difluorophenyl)-5-fluoro-2-formylpyridin-3-yl]carbamate(Prepared in Example 108, Step 2; 18 mg, 0.050 mmol) were dissolved intoluene (2.0 mL) and catalitic amount of acetic acid was added. Thereaction mixture was heated at 100° C. for 2 h. Then solvent wasevaporated and methanol (2.0 mL) was added. After addition of sodiumtetrahydroborate (4.3 mg, 0.11 mmol), the reaction mixture was stirredfor 30 min, then concentrated under reduced pressure.

The residue was dissolved in methanol (0.5 mL) and 4.0 M hydrogenchloride in dioxane (2 mL) was added, the mixture was stirred for 30min. Solvent was removed and the residue was purified with prep-HPLC(Waters Sunfire C18, 5 um particle size, 30×100 mm; mobile phases: water(0.1% TFA)/acetonitrile at a flow rate of 60 ml/min) to give the desiredproduct (11.5 mg, 70%). LCMS calc. for C₂₃H₂₄F₅N₆ (M+H)⁺ m/z: 479.2.found: 497.1. ¹H NMR (DMSO-d₆, 300 MHz): δ 8.05 (s, 1H); 7.85 (d, 1H);7.65 (m, 1H); 7.20 (m. 2H); 7.00 (d, 1H); 6.90 (d, 1H); 6.05 (s, 2H);5.90 (m, 1H); 4.30 (d, 1H); 4.15 (d, 1H); 3.10 (d, 1H); 2.65 (m, 1H);2.30 (m, 4H); 1.85 (d, 1H); 1.10 (m, 1H) ppm.

Example 1104-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-N-{[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}-2-fluoropyridin-3-amine

Step 1. tert-Butyl[(3S,5R)-1-(2-fluoro-3-nitropyridin-4-yl)-5-methylpiperidin-3-yl]carbamate

A mixture of 2,4-difluoro-3-nitropyridine (from Combi-Blocks, 0.20 g,1.2 mmol), tert-butyl [(3 S,5R)-5-methylpiperidin-3-yl]carbamate(Prepared in Intermediate 2, Step 4; 0.31 g, 1.4 mmol) and triethylamine(0.06 mL, 0.4 mmol) in isopropyl alcohol (0.29 mL) was stirred at r.tfor 1 h. The solvent was removed by rotavap and the residue was purifiedwith combi-flash with EtOAc/hexanes (10-60%) to give the desired product(0.40 g, 90%). LCMS calc. for C₁₆H₂₄FN₄O₄(M+H)⁺ m/z: 355.2. found:355.2.

Step 2. tert-Butyl[(3S,5R)-1-(3-amino-2-fluoropyridin-4-yl)-5-methylpiperidin-3-yl]carbamate

A mixture of tert-butyl [(3S,5R)-1-(2-fluoro-3-nitropyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(0.40 g, 1.2 mmol), methanol (20 mL) and 10% palladium on carbon (0.49g) was hydrogenated under positive pressure of H₂ at room temperaturefor 2 h. The reaction mixture was filtered and concentrated underreduced pressure to give the desired product (0.35 g, 90%). LCMS calc.for C₁₅H₂₄FN₄O₂(M+H)⁺ m/z: 311.2. found: 311.2.

Step 3. tert-Butyl[(3S,5R)-1-(3-{[(6-bromo-5-fluoropyridin-2-yl)methyl]amino}-2-fluoropyridin-4-yl)-5-methylpiperidin-3-yl]carbamate

tert-Butyl [(3S,5R)-1-(3-amino-2-fluoropyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(290 mg, 0.89 mmol) and 6-bromo-5-fluoropyridine-2-carbaldehyde(Prepared in Intermediate 1, Step 2; 200 mg, 0.980 mmol) were dissolvedin toluene (39 mL) and catalitic amount of acetic acid was added. Thereaction mixture was heated at 110° C. for 2 h. Then solvent wasevaporated and methanol (39 mL) was added. After addition of sodiumtetrahydroborate (84 mg, 2.2 mmol), the reaction mixture was stirred for30 min. Solvent was removed and the resulting residue was purified withCombi-flash chromatography with 20-100% EtOAc/hexane as eluents to givethe desired product as yellow solid (0.40 g, 85%). LCMS calc. forC₂₂H₂₉BrF₂N₅O₂ (M+H)⁺ m/z: 512.2. found: 512.1.

Step 4.4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-N-{[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}-2-fluoropyridin-3-amine

In a microwave tube, a mixture tert-butyl [(3S,5R)-1-(3-{[(6-bromo-5-fluoropyridin-2-yl)methyl]amino}-2-fluoropyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(50 mg, 0.1 mmol), (2,6-difluorophenyl)boronic acid (from Aldrich, 20mg, 0.13 mmol), and N,N-diisopropylethylamine (0.051 mL, 0.29 mmol) in1,4-dioxane (2.7 mL) and water (0.26 mL) was stirred together and purgedwith N₂ for 5 min before bis(tri-t-butylphosphine)palladium (10 mg, 0.03mmol) was added. The reaction mixture was then heated at 110° C. for 1h. The reaction mixture was worked up with NaHCO₃ solution and EtOAc.Layers were separated and the organic layer was dried and concentrated.The resultant residue was dissolved in small amount of MeOH and 4 N HClwas added. The reaction mixture was stirred for 1 h at room temperatureSolvent was removed under reduced pressure and the residue was purifiedwith prep-HPLC (Waters Sunfire C18, 5 um particle size, 30×100 mm;mobile phases: water (0.15% ammonium hydroxide)/acetonitrile at a flowrate of 60 ml/min) to give the desired product (8.0 mg, 20%). LCMS calc.for C₂₃H₂₄F₄N₅ (M+H)⁺ m/z: 446.2. found: 446.1.

Example 1114-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-N-{1-[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]ethyl}pyridin-3-amine

Step 1.6-(2,6-Difluorophenyl)-5-fluoro-N-methoxy-N-methylpyridine-2-carboxamide

To a solution of 6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylicacid (0.97 g, 3.8 mmol) and N, O-dimethylhydroxylamine hydrochloride(0.357 g, 3.66 mmol) in DMF (10 mL) was addedN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (1.70 g, 4.47 mmol) and N,N-diisopropylethylamine(2.0 mL, 12 mmol). The reaction mixture was stirred at room temperatureovernight. The reaction mixture was diluted with water, extracted withDCM. The combined organic layers were dried over Na₂SO₄, filtered andconcentrated. The residue was purified with flash chromatography(eluting with 0-30% EtOAc in hexanes) to give the desired product (1.06g, 98%). LCMS calc. for C₁₄H₁₂F₃N₂O₂(M+H)⁺ m/z: 297.1. found: 297.1.

Step 2. 1-[6-(2,6-Difluorophenyl)-5-fluoropyridin-2-yl]ethanone

To a mixture of6-(2,6-difluorophenyl)-5-fluoro-N-methoxy-N-methylpyridine-2-carboxamide(1.06 g, 3.58 mmol) in tetrahydrofuran (20 mL) at 0° C. was added 3.0 Mmethylmagnesium bromide in ether (1.25 mL, 3.76 mmol) slowly. Thereaction mixture was stirred at 0° C. until complete conversion wasdetected by LCMS, then the reaction was quenched with NH₄Cl solution,and then the reaction mixture was extracted with EtOAc. The combinedorganic layers were washed with brine, dried and solvent evaporated. Theresidue was purified with flash chromatography (0-20% EtOAc in hexanes)to give the desired product as colorless solid.

Step 3.4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-N-{-[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]ethyl}pyridin-3-amine

To a mixture of sodium triacetoxyborohydride (147 mg, 0.694 mmol) in DCM(2.0 mL) was added trifluoroacetic acid (178 μL, 2.31 mmol). Afterstirring for 5 min, tert-butyl[(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate(Prepared in Intermediate 2, Step 6; 51.0 mg, 0.166 mmol) was addedfollowed by the addition of a solution of1-[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]ethanone (50 mg, 0.20mmol) in DCM (1 mL) dropwise. The reaction mixture was stirred for 3 h,then quenched with DCM and water. The organic layer was concentratedunder reduced pressure and purified with flash chromatography (0-15%methanol in DCM) to give the reductive amination product. Theintermediate was treated with 1:1 DCM/TFA (2 mL) and stirred for 1 h.The solvent was removed and the residue was dissolved in methanol andpurified with prep-LCMS (Waters Sunfire C18, 5 um particle size, 30×100mm; mobile phases: water (0.15% ammonium hydroxide)/acetonitrile at aflow rate of 60 ml/min) to give the desired product as white solid. LCMScalc. for C₂₄H₂₇F₃N₅ (M+H)⁺ m/z: 442.2. found: 442.2.

Example A Pim Enzyme Assays

Pim-1 and Pim-3 kinase assays-20 μL reactions were run in white 384 wellpolystyrene plates dotted with 0.8 μL compound/DMSO in the assay buffer(50 mM Tris, pH 7.5, 0.01% Tween-20, 5 mM mgCl₂, 0.01% BSA, 5 mM DTT),containing 0.05 M Biotin-labeled BAD peptide substrate (AnaSpec 62269),1 mM ATP, and 2.5 pM (Pim-1, Invitrogen PV3503) or 1.25 pM (Pim-3,Millipore 14-738) enzyme for 1 h at 25° C. Reactions were stopped byaddition of 10 μL STOP Buffer (150 mM Tris, pH=7.5, 150 mM NaCl, 75 mMEDTA, 0.01% Tween-20, 0.3% BSA,) supplemented with Phospho-Bad (Ser112)Antibody (Cell Signaling 9291) diluted 666-fold, and Streptavidin donorbeads (PerkinElmer 6760002) along with Protein-A acceptor beads(PerkinElmer 6760137) at 15 μg/mL each. Supplementation of the STOPbuffer with beads and stopping the reactions were done under reducedlight. Prior to the stopping reactions STOP buffer with beads waspreincubated for 1 h in the dark at room temperature. After stopping thereactions, plates were incubated for 1 h in the dark at room temperaturebefore reading on a PHERAstar FS plate reader (BMG Labtech) underreduced light.

Pim-2 kinase assay-20 μL reactions were run in white 384 wellpolystyrene plates dotted with 0.8 μL compound/DMSO in the assay buffer(50 mM Tris, pH 7.5, 0.01% Tween-20, 5 mM mgCl₂, 0.01% BSA, 5 mM DTT),containing 0.05 M Fluorescein-labeled CREBtide peptide substrate(Invitrogen PV3508), 1 mM ATP, and 1 nM enzyme (Invitrogen PV3649) for 2h at 25° C. Reactions were stopped by addition of 10 μL TR-FRET DilutionBuffer (Invitrogen PV3574) with 30 mM EDTA and 1.5 nM LanthaScreenTb-CREB pSer133 antibody (Invitrogen PV3566). After 30 min. incubationat room temperature, plates were read on a PHERAstar FS plate reader(BMG Labtech).

Compounds of the invention having an IC₅₀ of 2 M or less when tested forPIM kinase activity under the assay conditions disclosed above areconsidered active.

Although the above in vitro assays are conducted at 1 mM ATP compoundscan also be evaluated for potency and in vitro activity against PIMtargets utilizing K_(m) conditions, where the concentration of ATP isset to the K_(m) value and the assay is more sensitive to PIM inhibitionactivity.

Example B Pim Cellular Assays

One or more compounds of the invention were tested for inhibitoryactivity of PIM according to at least one of the following cellularassays. Compounds of the invention having an IC₅₀ of 10 μM or less whentested for PIM kinase activity under the cellular assay conditionsdisclosed below would be and were considered active.

Pim Cell Proliferation Assays

KG-1A cells are purchased from ATCC (Manassas, Va.) and KMS.12.BM cellsare purchased from NIBIO, JCRB cell bank (Tokyo, Japan) and maintainedin the culture mediums recommended, RPMI, 10% FBS and IMDM 20% FBS(Mediatech, Manassas, Va.) respectively. To measure theanti-proliferation activity of test compounds, both cell lines areplated with the culture medium (2×10³ cells/well/in 200 μL) into 96-wellpolystyrene ultralow binding (Costar,) in the presence or absence of aconcentration range of test compounds. After 4 days, [³H]-thymidine, 1μCi/10 μL/well (PerkinElmer, Boston, Mass.) in culture medium is thenadded to the cell culture for an additional 16 h before the incorporatedradioactivity is separated by filtration with a Packard Micro plateHarvester with water through a 0.3% PEI pre wetted GF/B filter plates(Packard Bioscience/PerkinElmer, Boston, Mass.). The plate is measuredby liquid scintillation counting with a TopCount (PerkinElmer). IC₅₀determination is performed by fitting the curve of percent inhibitionversus the log of the inhibitor concentration using the GraphPad Prism5.0 software.

Pim Cell Proliferation Assay

MOLM-16 cells are purchased from DSMZ (Germany) and maintained in theculture medium recommended, RPMI, 20% FBS. To measure theanti-proliferation activity of test compounds, the cells are plated withthe RPMI, 10% FBS (1×10⁴ cells/well/in 200 μL) into 96-well polystyreneultralow binding plates (Costar) in the presence or absence of aconcentration range of test compounds. After 4 days, [³H]-thymidine, 1μCi/10 μL/well (PerkinElmer, Boston, Mass.) in RPMI, 10% FBS is thenadded to the cell culture for an additional 16 h before the incorporatedradioactivity is separated by filtration with a Packard Micro plateHarvester with water through a 0.3% PEI pre wetted GF/B filter plates(Packard Bioscience/PerkinElmer, Boston, Mass.). The plate is measuredby liquid scintillation counting with a TopCount (PerkinElmer). IC₅₀determination is performed by fitting the curve of percent inhibitionversus the log of the inhibitor concentration using the GraphPad Prism5.0 software.

Pim pBAD Signaling Assay

KG-1A cells are purchased from ATCC (Manassas, Va.) and KMS.12.BM cellsare purchased from NIBIO, JCRB cell bank (Tokyo, Japan) and maintainedin the culture mediums recommended, RPMI, 10% FBS and IMDM 20% FBS(Mediatech, Manassas, Va.) respectively. To measure the pBAD inhibitoryactivity of the compounds, both cell lines are plated with the culturemedium (1×10⁶/well/100 μL for KG1A and 4×10⁵ cells/well/in 100 μL forKMS12BM) into 96-well V bottom polypropylene plates (Matrix, ThermoFisher, USA) and incubated 30 min. at 37° C. to normalize cell signalingfrom handling. Test compounds are added at an appropriate concentrationrange and further incubated for 2.5 h for KMS. 12.BM cells and 4 h forKG1-A cells. Plates are centrifuged at 2000 RPM for 10 min. andsupernatants aspirated. 100 μL lysis buffer with protease inhibitors(Cell Signaling Technologies, Danver, Mass., Sigma, St Louis Mo., EMD,USA) is added to the pellets, mixed well and set on ice for 30 min.Lysates are frozen overnight at −80° C. To measure the pBAD activity, aCell Signaling ELISA kit (Cell Signaling Path Scan phosphor pBAD ELISA)is utilized. 50 μL of the lysate is tested per the ELISA protocol andthe data analysis is performed by software on a SpectrMax5 plate reader(Molecular Devices, Sunnyvale, Calif.). IC₅₀ determination is performedby fitting the curve of percent inhibition versus the log of theinhibitor concentration using the GraphPad Prism 5.0 software.

Data obtained for the Example compounds, obtained using the methodsdescribed in Example A, are provided in Table 1.

TABLE 1 Pim Enzyme Assay Data Pim1 Pim2 Pim3 Example No. IC₅₀ (nM)^(a)IC₅₀ (nM)^(b) IC₅₀ (nM)^(a)  1 * + *  2 * + *  3 * + *  4 * + *  5 * + * 6 * + *  7 * + *  8 * ++ *  9 * ++ * 10 * + * 11 * ++ * 12 * + *13 * + * 14 * + * 15 * ++ * 16 * ++ * 17 * ++ * 18 * ++ * 19 * + * 20 *+++ ** 21 * ++ * 22 * ++ * 23 * ++ * 24 * + *   24A * + *   24B * ++ *25 * ++ * 26 * ++ * 27 * ++ * 28 * ++ * 29 * ++ * 30 ** +++ ** 31 * +++** 32 * + * 33 * + * 34 * + * 35 * + * 36 * + * 37 * ++ * 38 * ++ *39 * + * 40 * ++ * 41 * ++ * 42 * + * 43 * + * 44 * + * 45 * + *46 * + * 47 * + * 48 * + * 49 * ++ * 50 * ++ * 51 * + * 52 * + *53 * + * 54 * + * 55 * + * 56 * + * 57 * ++ * 58 * ++ ** 59 * ++ * 60 *++ * 61 * + * 62 * + * 63 * + * 64 * + * 65 * + * 66 * ++ * 67 * ++ *68 * ++ * 69 * +++ * 70 * ++ * 71 * + * 72 * + * 73 * + * 74 * + *75 * + * 76 * + * 77 * + * 78 * + * 79 n/a n/a n/a 80 n/a n/a n/a 81 n/an/a n/a 82 * + * 83 * + * 84 * ++ * 85 * ++ * 86 * ++ * 87 * +++ **(Diastereoisomer 1) 87 * ++ ** (Diastereoisomer 2) 88 * +++ * 89 * ++ *90 * +++ * 91 * ++ * 92 * ++ * 93 * ++ * 94 n/a n/a n/a 95 n/a n/a n/a96 * ++ * 97 ** ++ * 98 * ++ * 99 * + * 100  * + * 101  n/a n/a n/a102  * ++ * 103  * + * 104  * ++ * 105  * + * 106  * + * 107  * + *108  * + * 109  * + * 110  * + * 111  * + * ^(a)IC₅₀ ≦ 10 nM: *; 10 nM <IC₅₀ ≦ 50 nM: **; 50 nM < IC₅₀ ≦ 500 nM: ***; 500 nM < IC₅₀ ≦ 2000 nM:****. Assays performed at 1 mM ATP. ^(b)IC₅₀ ≦ 100 nM: +; 100 nM < IC₅₀≦ 1000 nM: ++; 1000 nM < IC₅₀ ≦ 10000 nM: +++. Assays performed at 1 mMATP.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including withoutlimitation all patent, patent applications, and publications, cited inthe present application is incorporated herein by reference in itsentirety.

What is claimed is:
 1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: X is N or CH;ring A is C₆₋₁₀ aryl or 5-10 membered heteroaryl, said heteroaryl groupconsisting of one or more carbon atoms and 1, 2, or 3 heteroatomsselected from N, O and S, wherein the C₆₋₁₀ aryl or 5-10 memberedheteroaryl is optionally substituted with 1 or 2 substituentsindependently selected from R^(A); R^(A) is halogen, cyano, amino, orC₁₋₃ alkyl; n is 0 or 1; Cy^(A), when present, is selected from C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₇ cycloalkyl, and 4-10 memberedheterocycloalkyl, wherein the ring atoms of the 5-10 membered heteroarylor 4-10 membered heterocycloalkyl forming Cy^(A) consist of one or morecarbon atoms and 1, 2, or 3 heteroatoms selected from N, O and S, andwherein the C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₇ cycloalkyl, and4-10 membered heterocycloalkyl forming Cy^(A) are each optionallysubstituted by 1, 2 or 3 substituents independently selected fromR^(CyA); R^(CyA) is halogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, Cy^(B), -L-Cy^(B), ═O, CN, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),NR^(c1)R^(d1) NR^(c1)C(O)R^(b1), NR^(c1)C(O)NR^(c1)R^(d1),NR^(c1)C(O)OR^(a1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),NR^(c1)S(O)₂R^(b1) or S(O)₂NR^(c1)R^(d1); wherein the C₁₋₄ alkyl, C₂₋₄alkenyl, and C₂₋₄ alkynyl forming R^(CyA) are each optionallysubstituted with 1, 2 or 3 substituents independently selected fromhalogen, C₁₋₃ haloalkyl, CN, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)NR^(c1)R^(d1),NR^(c1)C(O)OR^(a1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),NR^(c1)S(O)₂R^(b1) and S(O)₂NR^(c1)R^(d1); Cy^(B) is selected from C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₇ cycloalkyl, and 4-10 memberedheterocycloalkyl, wherein the ring atoms of the 5-10 membered heteroarylor 4-10 membered heterocycloalkyl forming Cy^(A) consist of one or morecarbon atoms and 1, 2, or 3 heteroatoms selected from N, O and S, andwherein the C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₇ cycloalkyl, and4-10 membered heterocycloalkyl forming Cy^(B) are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR^(CyB); R^(CyB) is halogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, CN, OH, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2),C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2)NR^(c2)C(O)R^(b2), NR^(c2)C(O)NR^(c2)R^(d2) NR^(c2)C(O)OR^(a2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2) orS(O)₂NR^(c2)R^(d2), wherein the C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄alkynyl forming R^(CyB) are each optionally substituted with 1, 2 or 3substituents independently selected from halogen, C₁₋₃ haloalkyl, CN,OH, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2) NR^(c2)C(O)R^(b2)NR^(c2)C(O)NR^(c2)R^(d2) NR^(c2)C(O)OR^(a2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2) andS(O)₂NR^(c2)R^(d2); L is C₁₋₄ alkylene, L¹-O-L¹, L¹-C(═O)-L¹,L¹-OC(═O)-L¹, L¹-C(═O)O-L¹, L¹-NHC(═O)— L, L¹-C(═O)NH-L, L¹-NH-L¹,L¹-N(CH₃)-L¹, L¹-NHC(═O)NH-L, L¹-NHC(═O)O-L¹, L¹-S-L¹, L¹-S(═O)-L¹,L¹-S(═O)₂-L¹, L¹-NHS(═O)₂-L¹, L¹-S(═O)₂NH-L¹, L¹-NHS(═O)₂NH-L¹, whereinL¹, at each occurrence, is independently selected from a bond and C₁₋₂alkylene; and wherein the C₁₋₂ alkylene forming L¹ is optionallysubstituted with 1 or 2 substituents independently selected from F, Cl,CN, OH, O(C₁₋₃ alkyl), NH₂, NH(C₁₋₃ alkyl) and N(C₁₋₃ alkyl)₂; R¹ is H,F, Cl, CN, OH, C₁₋₃ alkoxy, —OC(O)O(C₁₋₃ alkyl), —OC(O)NH(C₁₋₃ alkyl),C₁₋₃ alkyl, C₁₋₃ haloalkyl, or C₃₋₆ cycloalkyl; R² is H, C₁₋₃ alkyl,C₁₋₃ haloalkyl or cyclopropyl; R³, R⁴, and R⁵ are each independentlyselected from H, halogen, OH, CN, amino, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂,C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl and C₁₋₄ haloalkoxy;alternatively, R⁴ and R⁵ in combination, together with the carbon atomsto which they are attached, form a 5, 6, or 7-membered fused aryl, a 5,6, or 7-membered fused cycloalkyl, a 5, 6, or 7-membered fusedheteroaryl, or a 5, 6, or 7-membered fused heterocycloalkyl, eachoptionally substituted by 1, 2 or 3 substituents independently selectedfrom halogen, OH, CN, amino, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkyl,C₁₋₄ alkoxy, C₁₋₄ haloalkyl and C₁₋₄ haloalkoxy; R⁶ and R⁷ are eachindependently selected from H, halogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, and C₁₋₄ haloalkyl; wherein said C₁₋₄ alkyl forming R⁶ or R⁷ isoptionally substituted with 1, 2, or 3 substituents independentlyselected from halogen, OH, CN, C₁₋₃ haloalkyl, C₁₋₄ alkoxy, OR^(a1),SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1) andS(O)₂NR^(c1)R^(d1); alternatively, R⁶ and R⁷, together with the carbonatom to which they are both attached, form a C₃₋₆ cycloalkyl group thatis optionally substituted with 1, 2, or 3 substituents independentlyselected from halogen, OH, CN, and C₁₋₄ alkyl; R^(a1), R^(b1), R^(c1)and R^(d1), at each occurrence, are independently selected from H, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, wherein said C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl groups forming R^(a1), R^(b1), R^(c1) and R^(d1)are each optionally substituted with 1, 2, or 3 substituentsindependently selected from C₁₋₄ alkyl, halo, CN, OR^(a2), SR^(a2),C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2) NR^(c2)C(O)R^(b2),NR^(c2)C(O)NR^(c2)R^(d2) NR^(c2)C(O)OR^(a2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2) andS(O)₂NR^(c2)R^(d2); or R^(c1) and R^(d1) attached to the same N atom,together with the N atom to which they are both attached, form a 4-, 5-,6-, or 7-membered heterocycloalkyl group that is optionally substitutedwith 1, 2, or 3 substituents independently selected from C₁₋₆ alkyl,halo, CN, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2) andS(O)₂NR^(c2)R^(d2); and R^(a2), R^(b2), R^(c2) and R^(d2) are eachindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl forming R^(a2), R^(b2), R^(c2) and R^(d2) are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, OH, CN, amino, NH(C₁₋₆ alkyl), N(C₁₋₆ alkyl)₂, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl and C₁₋₆ haloalkoxy.
 2. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein ringA is C₆₋₁₀ aryl optionally substituted with 1 or 2 substituents eachindependently selected from R^(A).
 3. The compound of claim 2, or apharmaceutically acceptable salt thereof, wherein ring A is phenyloptionally substituted with 1 or 2 substituents each independentlyselected from R^(A).
 4. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein ring A is 5-10 membered heteroaryloptionally substituted with 1 or 2 substituents each independentlyselected from R^(A).
 5. The compound of claim 4, or a pharmaceuticallyacceptable salt thereof, wherein ring A is a pyridinyl, pyrimidinyl,thiazolyl, quinolinyl, or furopyridinyl, each optionally substitutedwith 1 or 2 substituents each independently selected from R^(A).
 6. Thecompound of claim 5, or a pharmaceutically acceptable salt thereof,wherein each R^(A) is independently selected from F, NH₂, and isopropyl.7. The compound of claim 5, or a pharmaceutically acceptable saltthereof, wherein each R^(A) is F.
 8. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein n is
 0. 9. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein n is
 1. 10. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein Cy^(A) is C₆₋₁₀ aryl optionallysubstituted by 1, 2, or 3 substituents independently selected fromR^(CyA).
 11. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein Cy^(A) is phenyl optionally substituted by 1, 2,or 3 substituents independently selected from R^(CyA).
 12. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, whereinCy^(A) is 2-fluorophenyl optionally substituted by 1 or 2 substituentsindependently selected from R^(CyA).
 13. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein Cy^(A) is 5-10membered heteroaryl optionally substituted by 1, 2, or 3 substituentsindependently selected from R^(CyA).
 14. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein Cy^(A) is pyridinyl,benzothienyl, indolyl, dihydroindolyl, dihydrobenzofuranyl,imidazopyridinyl, or quinolinyl, each optionally substituted by 1, 2, or3 substituents independently selected from R^(CyA).
 15. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein Cy^(A)is pyridinyl, benzothien-5-yl, indolyl, dihydroindol-6-yl,1,3-dihydro-2H-indolinyl, 2,3-dihydrobenzofuran-6-yl,imidazo[1,2-a]pyridin-7-yl, or quinolinyl, each optionally substitutedby 1, 2, or 3 substituents independently selected from R^(CyA).
 16. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein Cy^(A) is C₃₋₇ cycloalkyl optionally substituted by 1, 2, or 3substituents independently selected from R^(CyA).
 17. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein Cy^(A)is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclohexenyl,each optionally substituted by 1, 2, or 3 substituents independentlyselected from R^(CyA).
 18. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein Cy^(A) is 4-10membered heterocycloalkyl optionally substituted by 1, 2, or 3substituents independently selected from R^(CyA).
 19. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein thecompound is according to any one of the following formulae (II-A) to(II-C):

wherein each n1 is 0, 1, or
 2. 20. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein the compound isaccording to any one of the following formulae (IV-A) to (IV-C):

wherein each n2 is 0 or
 1. 21. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein the compound isaccording to any one of the following formulae (IV-A) to (IV-C):


22. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein each R^(CyA) is halogen, C₁₋₄ alkyl, Cy^(B), -L-Cy^(B),CN, or OR^(a1); wherein each C₁₋₄ alkyl forming R^(CyA) is optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalogen, OR^(a1) and NR^(c1)R^(d1).
 23. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein Cy^(B) is C₆₋₁₀ aryloptionally substituted with 1, 2, or 3 substituents independentlyselected from R^(CyB).
 24. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein Cy^(B) is phenyloptionally substituted with 1, 2, or 3 substituents independentlyselected from R^(CyB).
 25. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein Cy^(B) is 5-10membered heteroaryl, optionally substituted with 1, 2, or 3 substituentsindependently selected from R^(CyB).
 26. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein Cy^(B) is pyridinyl,pyrazolyl, or quinolinyl, each optionally substituted with 1, 2, or 3substituents independently selected from R^(CyB).
 27. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein Cy^(B)is C₃₋₇ cycloalkyl, optionally substituted with 1, 2, or 3 substituentsindependently selected from R^(CyB).
 28. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein Cy^(B) is cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl or cyclohexenyl, each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR^(CyB).
 29. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein Cy^(B) is 4-10 membered heterocycloalkyl,optionally substituted with 1, 2, or 3 substituents independentlyselected from R^(CyB).
 30. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein Cy^(B) istetrahydrofuranyl, tetrahydropyranyl, morpholinyl, azetidinyl,pyrrolidinyl, or piperidinyl, each optionally substituted with 1, 2, or3 substituents independently selected from R^(CyB).
 31. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein eachR^(CyB) is H, halogen, C₁₋₄ alkyl, CN, OH, or OR^(a2).
 32. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ isH, F, or OH.
 33. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is H.
 34. The compound of claim 1,or a pharmaceutically acceptable salt thereof, wherein R¹ is OH.
 35. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R² is H.
 36. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R² is C₁₋₃ alkyl.
 37. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein R² ismethyl.
 38. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein R² is C₁₋₃ haloalkyl.
 39. The compound of claim 1,or a pharmaceutically acceptable salt thereof, wherein R² istrifluoromethyl.
 40. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R² is cyclopropyl.
 41. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein R³, R⁴,and R⁵ are each independently selected from H, halo, OH, CN, amino,NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyland C₁₋₄ haloalkoxy.
 42. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R³ is hydrogen.
 43. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein R⁴ ishydrogen.
 44. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein R⁵ is H.
 45. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R⁶ is selected from H,halogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₁₋₄ haloalkyl;wherein said C₁₋₄ alkyl forming R⁶ is optionally substituted with 1, 2or 3 substituents each independently selected from halogen, OH, CN, C₁₋₃haloalkyl, C₁₋₄ alkoxy, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1),C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1) andS(O)₂NR^(c1)R^(d1); and wherein R⁷ is H or C₁₋₄ alkyl.
 46. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁶and R⁷ are each independently selected from H and C₁₋₄ alkyl.
 47. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R⁶ is H.
 48. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R⁷ is H.
 49. The compound of claim 1,or a pharmaceutically acceptable salt thereof, wherein R⁶ and R⁷,together with the carbon atom to which they are both attached, form aC₃₋₆ cycloalkyl group that is optionally substituted with 1, 2 or 3substituents each independently selected from halogen, OH, CN, and C₁₋₄alkyl.
 50. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein R⁶ and R⁷, together with the carbon atom to whichthey are both attached, form an unsubstituted C₃₋₆ cycloalkyl.
 51. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R⁶ and R⁷, together with the carbon atom to which they are bothattached, form an unsubstituted cyclopropyl group.
 52. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein R^(a1),R^(b1), R^(c1), R^(d1), R^(a2), R^(b2), R^(c2) and R^(d2) are eachindependently selected from H and C₁₋₆ alkyl.
 53. The compound of claim1 selected from the following compounds, or a pharmaceuticallyacceptable salt thereof:3-amino-1-{3-[({6-[2,6-difluoro-4-(3-hydroxytetrahydrofuran-3-yl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;3-amino-1-(3-(((6-(2,6-difluoro-4-(1-hydroxycyclobutyl)phenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;3-amino-1-(3-(((6-(2,6-difluoro-4-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;3-(4-{6-[({4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)tetrahydrofuran-3-ol;1-(4-(6-((4-(3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-3,5-difluorophenyl)cyclobutanol;4-(4-(6-((4-(3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-3,5-difluorophenyl)tetrahydro-2H-pyran-4-ol;1-(4-{6-[({4-[3-amino-5-(trifluoromethyl)piperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)cyclobutanol;3-amino-1-{3-[({6-[2,6-difluoro-4-(1-hydroxycyclopropyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;3-amino-1-(3-(((6-(2,6-difluoro-3-(1-hydroxycyclopropyl)phenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;1-(4-{6-[({4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)cyclopropanol;1-(3-(6-((4-(3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-2,4-difluorophenyl)cyclopropanol;3-amino-1-{3-[({6-[2,6-difluoro-4-(2-hydroxy-2-methylpropyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;1-(4-{6-[({4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)-2-methylpropan-2-ol;3-amino-1-[3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-4-ol;3-amino-1-(3-(((5-fluoro-6-(2-fluoro-6-methoxyphenyl)pyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;3-amino-5-methyl-1-(3-(((3,3′,5′-trifluoro-[2,4′-bipyridin]-6-yl)methyl)amino)pyridin-4-yl)piperidin-4-ol;2-(6-((4-(3-amino-4-hydroxy-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-3-fluorobenzonitrile;3-amino-1-(3-(((5-fluoro-6-(2-fluorophenyl)pyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;4-[3-amino-5-methylpiperidin-1-yl]-N-{[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}pyridin-3-amine;4-(3-amino-5-methylpiperidin-1-yl)-N-((5-fluoro-6-(2-fluoro-6-methoxyphenyl)pyridin-2-yl)methyl)pyridin-3-amine;4-(3-amino-5-methylpiperidin-1-yl)-N-((3,3′,5′-trifluoro-2,4′-bipyridin-6-yl)methyl)pyridin-3-amine;2-(6-((4-(3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-3-fluorobenzonitrile;4-(3-amino-5-methylpiperidin-1-yl)-N-((5-fluoro-6-(2-fluorophenyl)pyridin-2-yl)methyl)pyridin-3-amine;2-(4-{6-[({4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)-2-methylpropanenitrile;2-(4-{6-[({4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)-2-methylpropanenitrile;3-amino-5-methyl-1-(3-{[(2′,6,6′-trifluorobiphenyl-3-yl)methyl]amino}pyridin-4-yl)piperidin-4-ol;4-[3-amino-5-methylpiperidin-1-yl]-N-[(2′,6,6′-trifluorobiphenyl-3-yl)methyl]pyridin-3-amine;1-(5′-((4-(3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-2,2′,6-trifluorobiphenyl-4-yl)cyclobutanol;4-(5′-((4-(3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-2,2′,6-trifluorobiphenyl-4-yl)tetrahydro-2H-pyran-4-ol;3-amino-1-[3-({[6-(2,6-difluorophenyl)pyridin-2-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-4-ol;4-[3-amino-5-methylpiperidin-1-yl]-N-{[6-(2,6-difluorophenyl)pyridin-2-yl]methyl}pyridin-3-amine;3-amino-1-[3-({[2-(2,6-difluorophenyl)pyrimidin-4-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-4-ol;4-[3-amino-5-methylpiperidin-1-yl]-N-{[2-(2,6-difluorophenyl)pyrimidin-4-yl]methyl}pyridin-3-amine;3-amino-1-(3-(((6-(2,6-difluoro-4-morpholinophenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;4-(3-amino-5-methylpiperidin-1-yl)-N-((6-(2,6-difluoro-4-morpholinophenyl)-5-fluoropyridin-2-yl)methyl)pyridin-3-amine;4-(3-amino-5-(trifluoromethyl)piperidin-1-yl)-N-((6-(2,6-difluoro-4-morpholinophenyl)-5-fluoropyridin-2-yl)methyl)pyridin-3-amine;3-amino-1-{3-[({6-[2,6-difluoro-4-(hydroxymethyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;(4-{6-[({4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)methanol;3-amino-1-[3-({[6-(5,7-difluoroquinolin-6-yl)-5-fluoropyridin-2-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-4-ol;4-[3-amino-5-methylpiperidin-1-yl]-N-{[6-(5,7-difluoroquinolin-6-yl)-5-fluoropyridin-2-yl]methyl}pyridin-3-amine;3-amino-1-{3-[({6-[2,6-difluoro-4-(morpholin-4-ylmethyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;3-amino-1-(3-(((6-(2,6-difluoro-4-((methylamino)methyl)phenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;3-amino-1-(3-(((6-(4-(azetidin-1-ylmethyl)-2,6-difluorophenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;3-amino-1-(3-(((6-(2,6-difluoro-4-((3-hydroxypyrrolidin-1-yl)methyl)phenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;1-(4-(6-((4-(3-amino-4-hydroxy-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-3,5-difluorobenzyl)pyrrolidine-3-carbonitrile;3-amino-1-(3-(((6-(2,6-difluoro-4-((3-fluoropyrrolidin-1-yl)methyl)phenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;4-[3-amino-5-methylpiperidin-1-yl]-N-({6-[2,6-difluoro-4-(morpholin-4-ylmethyl)phenyl]-5-fluoropyridin-2-yl}methyl)pyridin-3-amine;4-(3-amino-5-methylpiperidin-1-yl)-N-((6-(2,6-difluoro-4-((methylamino)methyl)phenyl)-5-fluoropyridin-2-yl)methyl)pyridin-3-amine;4-(3-amino-5-methylpiperidin-1-yl)-N-((6-(4-(azetidin-1-ylmethyl)-2,6-difluorophenyl)-5-fluoropyridin-2-yl)methyl)pyridin-3-amine;1-(4-(6-((4-(3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-3,5-difluorobenzyl)pyrrolidin-3-ol;1-(4-(6-((4-(3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-3,5-difluorobenzyl)pyrrolidine-3-carbonitrile;4-(3-amino-5-methylpiperidin-1-yl)-N-((6-(2,6-difluoro-4-((3-fluoropyrrolidin-1-yl)methyl)phenyl)-5-fluoropyridin-2-yl)methyl)pyridin-3-amine;3-amino-1-(3-{[(6-cyclohex-1-en-1-yl-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-4-ol;4-[3-amino-5-methylpiperidin-1-yl]-N-[(6-cyclohexyl-5-fluoropyridin-2-yl)methyl]pyridin-3-amine;3-amino-1-{3-[({6-[2,6-difluoro-4-(4-methoxytetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;4-[3-amino-5-methylpiperidin-1-yl]-N-({6-[2,6-difluoro-4-(4-methoxytetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)pyridin-3-amine;3-amino-1-{3-[({6-[2,6-difluoro-4-(4-fluorotetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;4-[3-amino-5-methylpiperidin-1-yl]-N-({6-[2,6-difluoro-4-(4-fluorotetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)pyridin-3-amine;3-amino-1-{3-[({6-[2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;4-[3-amino-5-methylpiperidin-1-yl]-N-({6-[2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)pyridin-3-amine;4-(3-amino-5-(trifluoromethyl)piperidin-1-yl)-N-((6-(2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl)-5-fluoropyridin-2-yl)methyl)pyridin-3-amine;4-[3-amino-5-methylcyclohexyl]-N-{[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}pyridin-3-amine;1-(4-{6-[({4-[3-amino-5-methylcyclohexyl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)cyclobutanol;4-[3-amino-5-methylcyclohexyl]-N-{[6-(2,6-difluoro-4-morpholin-4-ylphenyl)-5-fluoropyridin-2-yl]methyl}pyridin-3-amine;N-{[5-amino-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]methyl}-4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-amine;4-[3-amino-5-methylpiperidin-1-yl]-N-[(6-{2,6-difluoro-4-[3-fluoropyrrolidin-1-yl]phenyl}-5-fluoropyridin-2-yl)methyl]pyridin-3-amine;4-[3-amino-5-methylpiperidin-1-yl]-N-({6-[2,6-difluoro-4-(3-fluoropiperidin-1-yl)phenyl]-5-fluoropyridin-2-yl}methyl)pyridin-3-amine;1-(4-{6-[({4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)-3-methylazetidin-3-ol;3-amino-1-(3-{[(6-{2,6-difluoro-4-[tetrahydrofuran-3-yloxy]phenyl}-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-4-ol;4-[3-amino-5-methylpiperidin-1-yl]-N-[(6-{2,6-difluoro-4-[tetrahydrofuran-3-yloxy]phenyl}-5-fluoropyridin-2-yl)methyl]pyridin-3-amine;3-amino-1-{3-[({6-[2,6-difluoro-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;4-[3-amino-5-methylpiperidin-1-yl]-N-({6-[2,6-difluoro-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]-5-fluoropyridin-2-yl}methyl)pyridin-3-amine;4-[3-amino-5-methylpiperidin-1-yl]-N-[(6-{2,6-difluoro-4-[(1-methylpiperidin-4-yl)oxy]phenyl}-5-fluoropyridin-2-yl)methyl]pyridin-3-amine;3-amino-1-(3-{[(6-{4-[(3,3-difluorocyclobutyl)oxy]-2,6-difluorophenyl}-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-4-ol;4-[3-amino-5-methylpiperidin-1-yl]-N-[(6-{4-[(3,3-difluorocyclobutyl)oxy]-2,6-difluorophenyl}-5-fluoropyridin-2-yl)methyl]pyridin-3-amine;3-amino-1-[3-({[6-(2,6-difluoro-4-methoxyphenyl)-5-fluoropyridin-2-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-4-ol;4-[3-amino-5-methylpiperidin-1-yl]-N-{[6-(2,6-difluoro-4-methoxyphenyl)-5-fluoropyridin-2-yl]methyl}pyridin-3-amine;4-{6-[({4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3-fluorobenzonitrile;4-[3-amino-5-methylpiperidin-1-yl]-N-{[6-(1-benzothien-5-yl)-5-fluoropyridin-2-yl]methyl}pyridin-3-amine;6-{6-[({4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-1,3-dihydro-2H-indol-2-one;4-[3-amino-5-methylpiperidin-1-yl]-3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol;3-amino-1-[5-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}amino)-2,3-dihydrofuro[2,3-b]pyridin-4-yl]-5-methylpiperidin-4-ol;4-[3-amino-4-fluoropiperidin-1-yl]-N-{[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}pyridin-3-amine;4-[3-amino-5-methylpiperidin-1-yl]-N-{[7-(2,3-dihydro-1-benzofuran-6-yl)quinolin-2-yl]methyl}pyridin-3-amine;4-[3-amino-5-methylpiperidin-1-yl]-N-[(7-imidazo[1,2-a]pyridin-7-ylquinolin-2-yl)methyl]pyridin-3-amine;3-amino-1-(3-{[(7-imidazo[1,2-a]pyridin-7-ylquinolin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-4-ol;3-amino-1-{3-[({6-[2,6-difluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;3-amino-1-(3-{[(3-isopropylfuro[3,2-b]pyridin-5-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-4-ol;3-amino-1-(3-(((3-(2,6-difluoro-4-(hydroxymethyl)phenyl)furo[3,2-b]pyridin-5-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;3-amino-1-(3-(((3-(2-fluoro-4-(hydroxymethyl)phenyl)furo[3,2-b]pyridin-5-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;4-[3-amino-5-methylpiperidin-1-yl]-N-[(3-isopropylfuro[3,2-b]pyridin-5-yl)methyl]pyridin-3-amine;(4-(5-((4-(3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)furo[3,2-b]pyridin-3-yl)-3,5-difluorophenyl)methanol;(4-(5-((4-(3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)furo[3,2-b]pyridin-3-yl)-3-fluorophenyl)methanol;3-amino-1-(3-{[(3-cyclopropylfuro[3,2-b]pyridin-5-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-4-ol;4-[3-amino-5-methylpiperidin-1-yl]-N-[(3-cyclopropylfuro[3,2-b]pyridin-5-yl)methyl]pyridin-3-amine;1-(4-{6-[({4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenoxy)-2-methylpropan-2-ol;3-amino-1-{3-[({6-[2,6-difluoro-4-(2-hydroxy-2-methylpropoxy)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;2-(4-{6-[({4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)propan-2-ol;3-amino-1-{3-[({6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;4-{2-[({4-[3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]quinolin-7-yl}-3-fluoro-1-methylpyridin-2(1H)-one;2-[({4-[3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-6-(2,6-difluorophenyl)-5-fluoropyridin-3-amine;2-[({4-[3-amino-5-(trifluoromethyl)piperidin-1-yl]pyridin-3-yl}amino)methyl]-6-(2,6-difluorophenyl)-5-fluoropyridin-3-amine;4-[3-amino-5-methylpiperidin-1-yl]-N-{[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}-2-fluoropyridin-3-amine;and4-[3-amino-5-methylpiperidin-1-yl]-N-{1-[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]ethyl}pyridin-3-amine.54. The compound of claim 1 selected from the following compounds, or apharmaceutically acceptable salt thereof:(3R,4R,5S)-3-amino-1-{3-[({6-[2,6-difluoro-4-(3-hydroxytetrahydrofuran-3-yl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;(3R,4R,5S)-3-amino-1-(3-(((6-(2,6-difluoro-4-(1-hydroxycyclobutyl)phenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;(3R,4R,5S)-3-amino-1-(3-(((6-(2,6-difluoro-4-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;3-(4-{6-[({4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)tetrahydrofuran-3-ol;1-(4-(6-((4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-3,5-difluorophenyl)cyclobutanol;4-(4-(6-((4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-3,5-difluorophenyl)tetrahydro-2H-pyran-4-ol;1-(4-{6-[({4-[(3S,5R)-3-amino-5-(trifluoromethyl)piperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)cyclobutanol;(3R,4R,5S)-3-amino-1-{3-[({6-[2,6-difluoro-4-(1-hydroxycyclopropyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;(3R,4R,5S)-3-amino-1-(3-(((6-(2,6-difluoro-3-(1-hydroxycyclopropyl)phenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;1-(4-{6-[({4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)cyclopropanol;1-(3-(6-((4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-2,4-difluorophenyl)cyclopropanol;(3R,4R,5S)-3-amino-1-{3-[({6-[2,6-difluoro-4-(2-hydroxy-2-methylpropyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;1-(4-{6-[({4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)-2-methylpropan-2-ol;(3R,4R,5S)-3-amino-1-[3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-4-ol;(3R,4R,5S)-3-amino-1-(3-(((5-fluoro-6-(2-fluoro-6-methoxyphenyl)pyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;(3R,4R,5S)-3-amino-5-methyl-1-(3-(((3,3′,5′-trifluoro-[2,4′-bipyridin]-6-yl)methyl)amino)pyridin-4-yl)piperidin-4-ol;2-(6-((4-((3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-3-fluorobenzonitrile;(3R,4R,5S)-3-amino-1-(3-(((5-fluoro-6-(2-fluorophenyl)pyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-{[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}pyridin-3-amine;4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)-N-((5-fluoro-6-(2-fluoro-6-methoxyphenyl)pyridin-2-yl)methyl)pyridin-3-amine;4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)-N-((3,3′,5′-trifluoro-2,4′-bipyridin-6-yl)methyl)pyridin-3-amine;2-(6-((4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-3-fluorobenzonitrile;4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)-N-((5-fluoro-6-(2-fluorophenyl)pyridin-2-yl)methyl)pyridin-3-amine;2-(4-{6-[({4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)-2-methylpropanenitrile;2-(4-{6-[({4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)-2-methylpropanenitrile;(3R,4R,5S)-3-amino-5-methyl-1-(3-{[(2′,6,6′-trifluorobiphenyl-3-yl)methyl]amino}pyridin-4-yl)piperidin-4-ol;4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-[(2′,6,6′-trifluorobiphenyl-3-yl)methyl]pyridin-3-amine;1-(5′-((4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-2,2′,6-trifluorobiphenyl-4-yl)cyclobutanol;4-(5′-((4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-2,2′,6-trifluorobiphenyl-4-yl)tetrahydro-2H-pyran-4-ol;(3R,4R,5S)-3-amino-1-[3-({[6-(2,6-difluorophenyl)pyridin-2-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-4-ol;4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-{[6-(2,6-difluorophenyl)pyridin-2-yl]methyl}pyridin-3-amine;(3R,4R,5S)-3-amino-1-[3-({[2-(2,6-difluorophenyl)pyrimidin-4-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-4-ol;4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-{[2-(2,6-difluorophenyl)pyrimidin-4-yl]methyl}pyridin-3-amine;(3R,4R,5S)-3-amino-1-(3-(((6-(2,6-difluoro-4-morpholinophenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)-N-((6-(2,6-difluoro-4-morpholinophenyl)-5-fluoropyridin-2-yl)methyl)pyridin-3-amine;4-((3S,5R)-3-amino-5-(trifluoromethyl)piperidin-1-yl)-N-((6-(2,6-difluoro-4-morpholinophenyl)-5-fluoropyridin-2-yl)methyl)pyridin-3-amine;(3R,4R,5S)-3-amino-1-{3-[({6-[2,6-difluoro-4-(hydroxymethyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;(4-{6-[({4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)methanol;(3R,4R,5S)-3-amino-1-[3-({[6-(5,7-difluoroquinolin-6-yl)-5-fluoropyridin-2-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-4-ol;4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-{[6-(5,7-difluoroquinolin-6-yl)-5-fluoropyridin-2-yl]methyl}pyridin-3-amine;(3R,4R,5S)-3-amino-1-{3-[({6-[2,6-difluoro-4-(morpholin-4-ylmethyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;(3R,4R,5S)-3-amino-1-(3-(((6-(2,6-difluoro-4-((methylamino)methyl)phenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;(3R,4R,5S)-3-amino-1-(3-(((6-(4-(azetidin-1-ylmethyl)-2,6-difluorophenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;(3R,4R,5S)-3-amino-1-(3-(((6-(2,6-difluoro-4-(((R)-3-hydroxypyrrolidin-1-yl)methyl)phenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;(3R,4R,5S)-3-amino-1-(3-(((6-(2,6-difluoro-4-(((S)-3-hydroxypyrrolidin-1-yl)methyl)phenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;(R)-1-(4-(6-((4-((3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-3,5-difluorobenzyl)pyrrolidine-3-carbonitrile;(S)-1-(4-(6-((4-((3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-3,5-difluorobenzyl)pyrrolidine-3-carbonitrile;(3R,4R,5S)-3-amino-1-(3-(((6-(2,6-difluoro-4-(((R)-3-fluoropyrrolidin-1-yl)methyl)phenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;(3R,4R,5S)-3-amino-1-(3-(((6-(2,6-difluoro-4-(((S)-3-fluoropyrrolidin-1-yl)methyl)phenyl)-5-fluoropyridin-2-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-({6-[2,6-difluoro-4-(morpholin-4-ylmethyl)phenyl]-5-fluoropyridin-2-yl}methyl)pyridin-3-amine;4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)-N-((6-(2,6-difluoro-4-((methylamino)methyl)phenyl)-5-fluoropyridin-2-yl)methyl)pyridin-3-amine;4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)-N-((6-(4-(azetidin-1-ylmethyl)-2,6-difluorophenyl)-5-fluoropyridin-2-yl)methyl)pyridin-3-amine;(R)-1-(4-(6-((4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-3,5-difluorobenzyl)pyrrolidin-3-ol;(S)-1-(4-(6-((4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-3,5-difluorobenzyl)pyrrolidin-3-ol;(R)-1-(4-(6-((4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-3,5-difluorobenzyl)pyrrolidine-3-carbonitrile;(S)-1-(4-(6-((4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)-3-fluoropyridin-2-yl)-3,5-difluorobenzyl)pyrrolidine-3-carbonitrile;4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)-N-((6-(2,6-difluoro-4-(((R)-3-fluoropyrrolidin-1-yl)methyl)phenyl)-5-fluoropyridin-2-yl)methyl)pyridin-3-amine;4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)-N-((6-(2,6-difluoro-4-(((S)-3-fluoropyrrolidin-1-yl)methyl)phenyl)-5-fluoropyridin-2-yl)methyl)pyridin-3-amine;(3R,4R,5S)-3-amino-1-(3-{[(6-cyclohex-1-en-1-yl-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-4-ol;4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-[(6-cyclohexyl-5-fluoropyridin-2-yl)methyl]pyridin-3-amine;(3R,4R,5S)-3-amino-1-{3-[({6-[2,6-difluoro-4-(4-methoxytetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-({6-[2,6-difluoro-4-(4-methoxytetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)pyridin-3-amine;(3R,4R,5S)-3-amino-1-{3-[({6-[2,6-difluoro-4-(4-fluorotetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-({6-[2,6-difluoro-4-(4-fluorotetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)pyridin-3-amine;(3R,4R,5S)-3-amino-1-{3-[({6-[2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-({6-[2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)pyridin-3-amine;4-((3S,5R)-3-amino-5-(trifluoromethyl)piperidin-1-yl)-N-((6-(2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl)-5-fluoropyridin-2-yl)methyl)pyridin-3-amine;4-[(1R,3S,5S)-3-amino-5-methylcyclohexyl]-N-{[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}pyridin-3-amine;1-(4-{6-[({4-[(1R,3S,5S)-3-amino-5-methylcyclohexyl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)cyclobutanol;4-[(1R,3S,5S)-3-amino-5-methylcyclohexyl]-N-{[6-(2,6-difluoro-4-morpholin-4-ylphenyl)-5-fluoropyridin-2-yl]methyl}pyridin-3-amine;N-{[5-amino-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]methyl}-4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-amine;4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-[(6-{2,6-difluoro-4-[(3R)-3-fluoropyrrolidin-1-yl]phenyl}-5-fluoropyridin-2-yl)methyl]pyridin-3-amine;4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-({6-[2,6-difluoro-4-(3-fluoropiperidin-1-yl)phenyl]-5-fluoropyridin-2-yl}methyl)pyridin-3-amine;1-(4-{6-[({4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)-3-methylazetidin-3-ol;(3R,4R,5S)-3-amino-1-(3-{[(6-{2,6-difluoro-4-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-4-ol;4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-[(6-{2,6-difluoro-4-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-5-fluoropyridin-2-yl)methyl]pyridin-3-amine;(3R,4R,5S)-3-amino-1-(3-{[(6-{2,6-difluoro-4-[(3S)-tetrahydrofuran-3-yloxy]phenyl}-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-4-ol;4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-[(6-{2,6-difluoro-4-[(3S)-tetrahydrofuran-3-yloxy]phenyl}-5-fluoropyridin-2-yl)methyl]pyridin-3-amine;(3R,4R,5S)-3-amino-1-{3-[({6-[2,6-difluoro-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-({6-[2,6-difluoro-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]-5-fluoropyridin-2-yl}methyl)pyridin-3-amine;4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-[(6-{2,6-difluoro-4-[(1-methylpiperidin-4-yl)oxy]phenyl}-5-fluoropyridin-2-yl)methyl]pyridin-3-amine;(3R,4R,5S)-3-amino-1-(3-{[(6-{4-[(3,3-difluorocyclobutyl)oxy]-2,6-difluorophenyl}-5-fluoropyridin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-4-ol;4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-[(6-{4-[(3,3-difluorocyclobutyl)oxy]-2,6-difluorophenyl}-5-fluoropyridin-2-yl)methyl]pyridin-3-amine;(3R,4R,5S)-3-amino-1-[3-({[6-(2,6-difluoro-4-methoxyphenyl)-5-fluoropyridin-2-yl]methyl}amino)pyridin-4-yl]-5-methylpiperidin-4-ol;4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-{[6-(2,6-difluoro-4-methoxyphenyl)-5-fluoropyridin-2-yl]methyl}pyridin-3-amine;4-{6-[({4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3-fluorobenzonitrile;4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-{[6-(1-benzothien-5-yl)-5-fluoropyridin-2-yl]methyl}pyridin-3-amine;6-{6-[({4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-1,3-dihydro-2H-indol-2-one;(7R)-4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol;(3R,4R,5S)-3-amino-1-[5-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}amino)-2,3-dihydrofuro[2,3-b]pyridin-4-yl]-5-methylpiperidin-4-ol;4-[(3R,4R)-3-amino-4-fluoropiperidin-1-yl]-N-{[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}pyridin-3-amine;4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-{[7-(2,3-dihydro-1-benzofuran-6-yl)quinolin-2-yl]methyl}pyridin-3-amine;4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-[(7-imidazo[1,2-a]pyridin-7-ylquinolin-2-yl)methyl]pyridin-3-amine;(3R,4R,5S)-3-amino-1-(3-{[(7-imidazo[1,2-a]pyridin-7-ylquinolin-2-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-4-ol;(3R,4R,5S)-3-amino-1-{3-[({6-[2,6-difluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;(3R,4R,5S)-3-amino-1-(3-{[(3-isopropylfuro[3,2-b]pyridin-5-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-4-ol;(3R,4R,5S)-3-amino-1-(3-(((3-(2,6-difluoro-4-(hydroxymethyl)phenyl)furo[3,2-b]pyridin-5-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;(3R,4R,5S)-3-amino-1-(3-(((3-(2-fluoro-4-(hydroxymethyl)phenyl)furo[3,2-b]pyridin-5-yl)methyl)amino)pyridin-4-yl)-5-methylpiperidin-4-ol;4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-[(3-isopropylfuro[3,2-b]pyridin-5-yl)methyl]pyridin-3-amine;(4-(5-((4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)furo[3,2-b]pyridin-3-yl)-3,5-difluorophenyl)methanol;(4-(5-((4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)pyridin-3-ylamino)methyl)furo[3,2-b]pyridin-3-yl)-3-fluorophenyl)methanol;(3R,4R,5S)-3-amino-1-(3-{[(3-cyclopropylfuro[3,2-b]pyridin-5-yl)methyl]amino}pyridin-4-yl)-5-methylpiperidin-4-ol;4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-[(3-cyclopropylfuro[3,2-b]pyridin-5-yl)methyl]pyridin-3-amine;1-(4-{6-[({4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenoxy)-2-methylpropan-2-ol;(3R,4R,5S)-3-amino-1-{3-[({6-[2,6-difluoro-4-(2-hydroxy-2-methylpropoxy)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;2-(4-{6-[({4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-3-fluoropyridin-2-yl}-3,5-difluorophenyl)propan-2-ol;(3R,4R,5S)-3-amino-1-{3-[({6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridin-2-yl}methyl)amino]pyridin-4-yl}-5-methylpiperidin-4-ol;4-{2-[({4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]quinolin-7-yl}-3-fluoro-1-methylpyridin-2(1H)-one;2-[({4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)methyl]-6-(2,6-difluorophenyl)-5-fluoropyridin-3-amine;2-[({4-[(3S,5R)-3-amino-5-(trifluoromethyl)piperidin-1-yl]pyridin-3-yl}amino)methyl]-6-(2,6-difluorophenyl)-5-fluoropyridin-3-amine;4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-{[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]methyl}-2-fluoropyridin-3-amine;and4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-N-{1-[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]ethyl}pyridin-3-amine.55. A composition comprising a compound of claim 1, or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier.
 56. A method of inhibiting Pim1,Pim2, or Pim3 enzyme comprising contacting the enzyme with a compound ofclaim 1, or a pharmaceutically acceptable salt thereof.
 57. A method ofinhibiting Pim1 enzyme comprising contacting the enzyme with a compoundof claim 1, or a pharmaceutically acceptable salt thereof.
 58. A methodof inhibiting Pim2 enzyme comprising contacting the enzyme with acompound of claim 1, or a pharmaceutically acceptable salt thereof. 59.A method of inhibiting Pim3 enzyme comprising contacting the enzyme witha compound of claim 1, or a pharmaceutically acceptable salt thereof.60. A method of treating a disease or condition that is associated withan elevated level of expression or activity at least one of Pim1, Pim2and Pim3, comprising administering to a patient in need of suchtreatment a therapeutically effective amount of a compound of claim 1,or a pharmaceutically acceptable salt thereof.
 61. A method of treatingcancer comprising administering to a patient in need of such treatment atherapeutically effective amount of a compound of claim 1, or apharmaceutically acceptable salt thereof.
 62. The method of claim 61,wherein the cancer is a cancer wherein the expression or activity of atleast one of Pim1, Pim2, and Pim3 is upregulated.
 63. The method ofclaim 61, wherein the cancer is a cancer wherein an oncogene isactivated.
 64. The method of claim 61, wherein the cancer is a cancerwherein Myc or Bcl2 is activated.
 65. The method of claim 61, whereinthe cancer is a solid tumor or a hematological cancer.
 66. The method ofclaim 61, wherein the cancer is prostate cancer, colon cancer,esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer,renal cancer, hepatic cancer, pancreatic cancer, gastric cancer, breastcancer, lung cancer, cancer of the head or neck, thyroid cancer,glioblastoma, sarcoma, bladder cancer, lymphoma, leukemia, acutelymphoblastic leukemia, acute myelogenous leukemia, chronic lymphocyticleukemia, chronic myelogenous leukemia, diffuse large-B cell lymphoma,mantle cell lymphoma, non-Hodgkin lymphoma, Hodgkin lymphoma or multiplemyeloma.
 67. A method of treating a myeloproliferative disorder,comprising administering to a patient in need of such treatment atherapeutically effective amount of a compound of claim 1, or apharmaceutically acceptable salt thereof, wherein the myeloproliferativedisorder is polycythemia vera, essential thrombocythemia, chronicmyelogenous leukemia, myelofibrosis, primary myelofibrosis, postpolycythemia vera/essential thrombocythemia myelofibrosis,post-essential thrombocythemia myelofibrosis or post polycythemia veramyelofibrosis.
 68. A method of treating an immune disorder comprisingadministering to a patient in need of such treatment a therapeuticallyeffective amount of a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein the immune disorder is multiplesclerosis, rheumatoid arthritis, allergy, food allergy, asthma, lupus,inflammatory bowel disease or ulcerative colitis, Crohn's disease,irritable bowel syndrome, pancreatitis, diverticulosis, Grave's disease,juvenile rheumatoid arthritis, osteoarthritis, psoriatic arthritis,ankylosing spondylitis, myasthenia gravis, vasculitis, autoimmunethyroiditis, dermatitis, psoriasis, scleroderma, systemic sclerosis,vitiligo, graft vs host disease, Sjogren's syndrome, glomerulonephritisor type I diabetes mellitis.
 69. A method of treating atherosclerosiscomprising administering to a patient in need of such treatment atherapeutically effective amount of a compound of claim 1, or apharmaceutically acceptable salt thereof.
 70. A method of reducingangiogenesis or tumor metastasis, comprising administering to a patientin need of such treatment a therapeutically effective amount of acompound of claim 1, or a pharmaceutically acceptable salt thereof.